NLRP3¶

June 14, 2026
in Weekly Digest, cGAS-STING, NLRP3, POLG-mtDNA, VDAC1
17 min read

SAMHD1 Research Digest — 2026-06-14

Generated by samhd1_monitor | Model: claude-sonnet-4-6

Summary: 41 papers evaluated | 12 high-relevance (≥7) | 17 medium (5–6) | 12 low (3–4) | 0 scored <3

🔴 High Relevance (Score 7–10)

Added to Zotero automatically

Spotlight on cGAS-STING: role in disease pathogenesis and therapeutic potential. (from Ophthalmology (senior author Liu Zuguo is an ophthalmologist, suggesting ocular surface/corneal innate immunity application))
Yan Dan; Hu Jiaoyue; Liu Zuguo; Ouyang Weijie — 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, ISG15-mitophagy, JAK-STAT, NLRP3, POLG-mtDNA, treatment-target, AGS-spectrum, ME-CFS

This comprehensive review directly covers the BLUE stream (cGAS→cGAMP→STING→IRF3→IFN-I) that is central to the SAMHD1 A565T mechanism, including mitochondrial/micronuclear DNA sensing, liquid-liquid phase separation dynamics, metabolic-immune crosstalk, neurodegenerative and autoimmune contexts, and emerging small-molecule inhibitors (including cGAS inhibitors like IMSB301-class compounds) that represent direct therapeutic targets for this interferonopathy.
DOI: 10.1186/s43556-026-00478-5

Mitochondria as convergence hubs for innate immunity pathways. (from Cell biology / mitochondrial biology)
Guo Yunhao; Xue Yansong — 2026
Score: 8/10 | Pathways: cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy, POLG-mtDNA, ME-CFS, other

This review directly addresses the convergence of mitochondria as innate immune signaling hubs integrating cGAS-STING, NLRP3, and MAVS pathways through mitochondrial DAMPs—precisely the mechanistic framework (BLUE, PURPLE, RED streams) underlying the SAMHD1 A565T interferonopathy, linking mitochondrial dysfunction to autoimmunity and offering therapeutic pathway insights.
DOI: 10.1038/s42003-026-10479-3

Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer's disease pathogenesis. (from Neurology/Neuroimmunology)
Liu Yongqing; Ye Yingzhi; Fan Minghua; Cheng Henry Yi; Sun Shuying — 2026
Score: 8/10 | Pathways: cGAS-STING, NLRP3, POLG-mtDNA, dNTPase, treatment-target, other

This paper directly demonstrates the mechanistic axis of cytosolic mtDNA release → cGAS-STING → NLRP3 chronic neuroinflammation in microglia, and critically implicates Cmpk2 (a mitochondrial dNTP kinase regulating mtDNA synthesis) as a regulatory node—directly paralleling SAMHD1's role in dNTP pool control and mtDNA-driven innate immune activation in the BLUE and PURPLE pathways, with KAT7 inhibition as a pharmacologically tractable intervention point.
DOI: 10.1016/j.neuron.2026.05.015

A pore is a pore is a pore (or a hub?): VDAC oligomerization in mitochondrial connectivity and modulation. (from Structural biology / mitochondrial biophysics)
De Pinto Vito; Battiato Giuseppe; Conti-Nibali Stefano; Cubisino Salvatore Anton — 2026
Score: 8/10 | Pathways: VDAC1, cGAS-STING, NLRP3, POLG-mtDNA, treatment-target, ISG15-mitophagy

This review directly covers VDAC1 oligomerization, macropore formation, mtDNA escape mechanisms, outer mitochondrial membrane permeabilization, and emerging small-molecule modulators (including VBIT-4 class compounds), all of which are central to the BLUE stream (SAMHD1/VDAC1 interaction loss → VDAC1 macropore → cytosolic mtDNA → cGAS-STING-IRF3-IFN-I) in the disease mechanism, and discusses therapeutic targeting strategies directly applicable to this interferonopathy.
DOI: 10.1042/bst20250480

Mitochondrial kinase CMPK2 in immune homeostasis and disease: from metabolic regulation to inflammatory signaling. (from Biochemistry/Virology)
Junhu Yao; Mengjie Shi; Siyan Chen; Huan Zhang; Yiming Lin — International immunopharmacology 2026
Score: 8/10 | Pathways: cGAS-STING, NLRP3, POLG-mtDNA, dNTPase, ME-CFS, treatment-target, other

CMPK2 is a mitochondrial nucleotide kinase that directly links mitochondrial dNTP pool regulation (UTP/CTP synthesis for mtDNA replication) to both NLRP3 inflammasome activation and cGAS-STING signaling via oxidized/escaped mtDNA, positioning it as a mechanistic neighbor to SAMHD1's dNTPase deficiency cascade, with additional relevance to SARS-CoV-2/post-viral contexts and SLE interferonopathy overlapping the AGS spectrum.
DOI: 10.1016/j.intimp.2026.116582

MitoSafe hypothesis: safeguarding mitochondrial morphology and innate immunity. (from Cell biology / mitochondrial biology)
Nora Haggerty; Kentaro Nakamura; H. Sesaki; M. Iijima — Trends in cell biology 2026
Score: 8/10 | Pathways: cGAS-STING, ISG15-mitophagy, VDAC1, POLG-mtDNA, ME-CFS

This paper directly addresses PINK1/Parkin-mediated mitophagy dysregulation leading to mitochondrial enlargement, mtDNA release, and STING-mediated inflammation — precisely the RED and BLUE pathway loops in the SAMHD1 haploinsufficiency mechanism where ISGylation of MFN1/MFN2 blocks PINK1/Parkin mitophagy, causing damaged mitochondrial accumulation, mtDNA escape, and cGAS-STING activation.
DOI: 10.1016/j.tcb.2026.04.007

Neuroprotection by lactate in Parkinson's disease: A novel anti-inflammatory mechanism via 14-3-3 protein lactylation. (from Neurology/Neurodegeneration (Parkinson's disease))
Zhang Qi; Liu Ming; Cao Wen-Jing; Zou Wei; Zhang Ping — 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, POLG-mtDNA, treatment-target, other

This paper directly demonstrates the mechanistic triad central to SAMHD1 haploinsufficiency pathology—NLRP3 inflammasome activation, cytosolic mtDNA release, and cGAS-STING pathway engagement—and shows that lactate/14-3-3 lactylation can interrupt this loop at multiple nodes (NLRP3 suppression → reduced GSDMD-driven mitochondrial injury → decreased cytosolic mtDNA → attenuated cGAS-STING), identifying lactate signaling as a novel upstream brake on the BLUE and PURPLE pathway convergence points relevant to the disease mechanism.
DOI: 10.1016/j.bbadis.2026.168314

A Narrative Review of the mtDNA-Stimulated Inflammatory Axis in Sepsis-Induced Acute Lung Injury: Cellular Mechanisms and Therapeutic Targeting. (from Critical care / pulmonology)
Ma Shuqi; Pan Qiusha; Zeng Ruifeng; Liu Quanle; Yang Suyi — 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, ISG15-mitophagy, treatment-target, other

This review directly covers the mtDNA-cGAS-STING-NLRP3 inflammatory axis with cell-type-specific mechanistic detail and therapeutic targeting strategies (STING inhibitors, MCC950-class NLRP3 blockers) that map precisely onto the BLUE and PURPLE pathways of SAMHD1 haploinsufficiency, where cytosolic mtDNA escape via VDAC1 macropores drives chronic interferonopathy and pyroptosis, making it highly mechanistically relevant even though SAMHD1 is not mentioned.
DOI: 10.1093/jleuko/qiag077

Small but mighty: mitochondrial DNA at the centre of retrograde signalling (from Cell biology / mitochondrial biology)
Eve Harding; Veronica Bazzani; C. Vascotto — Cell Communication and Signaling : CCS 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, ISG15-mitophagy, dNTPase, ME-CFS, other

This review directly addresses mtDNA escape, retrograde signalling via cGAS-STING innate immune activation, POLG/mtDNA instability, and mitochondrial dynamics—all core mechanistic streams of the SAMHD1 A565T syndrome—making it highly relevant as a mechanistic framework paper despite lacking direct SAMHD1 data.
DOI: 10.1186/s12964-026-02858-4

Mitochondrial DNA regulation of hepatic ischemia-reperfusion injury and intervention strategies (from hepatology/transplant surgery)
Ruotong Shen; Peng An; Meng Chen; Ping Lu; Jingjing Yang — Journal of Translational Medicine 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, ISG15-mitophagy, treatment-target, other

This paper directly elaborates the mtDNA-release → cGAS-STING → NLRP3 inflammasome → pyroptosis vicious cycle that constitutes the BLUE and PURPLE mechanistic streams of the SAMHD1 haploinsufficiency syndrome, covering VDAC1 permeability, mitophagy failure, and pharmacological intervention points (cGAS-STING and NLRP3 inhibition) directly relevant to therapeutic targeting in the family's interferonopathy.
DOI: 10.1186/s12967-026-08155-5

From symbiosis to immunity: the evolutionary revival of mitochondrial defense programs in inflammatory diseases (from Evolutionary biology / mitochondrial biology)
Weilong Hong; Shiyu Long; M. Ashrafizadeh; Gautam Sethi; Chenyang Duan — Cell Communication and Signaling : CCS 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy, POLG-mtDNA, ME-CFS, other

This review directly addresses the core convergence of mitochondrial dysfunction, mtDNA release, DAMP-driven innate immune activation (cGAS-STING, NLRP3), and mitophagy failure that constitutes the mechanistic heart of the SAMHD1 A565T interferonopathy model, including VDAC1-mediated mtDNA escape and the progression from mitochondrial stress to systemic inflammatory amplification, though SAMHD1 itself is not mentioned.
DOI: 10.1186/s12964-026-02736-z

Understanding cardiovascular aging as a disorder of mitochondrial network (from Cardiology)
Taslima Akter Shila; Dhrubo Ahmad; Jianli Zhao; Huilan Tan; Bo Wang — The Journal of Cardiovascular Aging 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, ISG15-mitophagy, POLG-mtDNA, NLRP3, treatment-target, clinical-phenotype

This review directly covers mtDNA release activating cGAS-STING, mitophagy/fission-fusion defects, and mitochondrial network dysfunction driving sterile inflammation — all core RED/BLUE/PURPLE stream mechanisms in the SAMHD1 haploinsufficiency model — with cardiovascular aging implications relevant to the family's interferonopathy-cardiac phenotype risk.
DOI: 10.20517/jca.2026.07

🟡 Medium Relevance (Score 5–6)

Review and add to Zotero manually if warranted

Targeting Mitochondria in Aging-Related Diseases: Therapeutic Potential and Obstacles. (from Geroscience/aging biology)
Xiang Zijie; Chen Yu; Liu Xishui; Lu Haowen; Yang Yuqing — 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy, POLG-mtDNA, mTOR-lysosomal, treatment-target, other

This review systematically covers mitochondrial dysfunction mechanisms directly relevant to the disease model—including cGAS-STING activation by escaped mtDNA, mitophagy failure, mitochondrial dynamics (MFN1/MFN2-related), biogenesis (PGC-1alpha), and mtDNA instability—and surveys therapeutic strategies (including mitochondrial transplantation and base editing) that could apply to SAMHD1 haploinsufficiency's convergent interferon-mitochondrial syndrome, though it does not address SAMHD1 specifically.
DOI: 10.1002/mco2.70790

Intrinsically Mitochondria-Targeting Nanozyme via Coordination-Assembly of Natural Quercetin for Cascade Antioxidant Therapy of Cerebral Ischemia-Reperfusion Injury. (from Nanomedicine/Neurology)
Zheng Wenxuan; Wang Zhicheng; Zhou Xin; Wang Shuya; Shi Xiaojing — 2026
Score: 6/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, treatment-target, other

This paper directly demonstrates the mtDNA leakage → cGAS-STING neuroinflammatory axis (core BLUE stream) and shows that stabilizing mitochondrial outer membrane proteins (including VDAC1-related outer membrane targets) prevents mtDNA escape, offering mechanistic and therapeutic parallels to the SAMHD1 haploinsufficiency syndrome's central pathogenic loop, though it is framed in cerebral ischemia-reperfusion rather than interferonopathy or SAMHD1 contexts.
DOI: 10.1002/advs.76038

Size-dependent ruthenium/ceria nanozymes synchronize catalytic ROS scavenging and electrostatic mtDNA sequestration for periodontitis therapy. (from Dental/biomaterials nanomedicine)
Zhang Fanrou; Qi Manlin; Liu Jia; Du Juanrui; Shi Fangyu — 2026
Score: 6/10 | Pathways: cGAS-STING, VDAC1, NLRP3, treatment-target, other

This paper directly addresses the mtDNA escape → cytosolic mtDNA → innate immune activation axis (core BLUE pathway) and mitochondrial oxidative stress, proposing electrostatic sequestration of cytosolic mtDNA as a therapeutic strategy that could conceptually apply to SAMHD1-driven cGAS-STING activation, though it is disease-specific to periodontitis and not mechanistically linked to SAMHD1 or dNTPase dysfunction.
DOI: 10.1186/s12951-026-04660-3

Sex Differences in Mitochondrial Function: Endocrine Regulation, Immunometabolic Signaling, and Implications for Health and Disease. (from Endocrinology/reproductive biology)
Bynum Hanna; Edwards Kristin S — 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy, JAK-STAT, ME-CFS, treatment-target, pregnancy-fetal, other

This review directly covers mtDNA release activating cGAS-STING, NLRP3 inflammasome, and mitochondrial quality control pathways central to the SAMHD1 A565T mechanism, and addresses sex-hormone modulation of mitochondrial biogenesis, ROS, and immunometabolic signaling that would modulate disease expression across the multi-generational family, but does not address SAMHD1 specifically or dNTP pool dynamics.
DOI: 10.3390/ijms27114966

No Correlation Between Interferon Signaling and Cytosolic Mitochondrial DNA/RNA Leakage in Cultured Skin Fibroblasts of Patients With Mitochondrial Diseases (from Mitochondrial disease / clinical genetics)
M. Marchais; Alessandra Pennisi; Alexandre Pierga; A. Lepelley; Nicolas Cagnard — European Journal of Immunology 2026
Score: 6/10 | Pathways: cGAS-STING, POLG-mtDNA, JAK-STAT, ME-CFS, other

This paper directly interrogates the cGAS-STING axis and cytosolic mtDNA leakage in patient fibroblasts with mitochondrial disease, finding that ISG elevation and mtDNA escape are dissociated—a critical negative finding that complicates the BLUE/PURPLE pathway model where VDAC1-mediated mtDNA escape drives IFN-I in SAMHD1 haploinsufficiency, and raises important methodological cautions about using fibroblast models to validate the proposed SAMHD1 A565T interferon-mitochondrial mechanism.
DOI: 10.1002/eji.70176

Advances in Elucidating the Mitochondrial DNA Mechanisms Underlying Ozone-Induced Inflammation (from Environmental toxicology/pulmonology)
Qian Chen; Hao Liu; Junhe Zhou; Yongjie Wei; Lingyan He — Toxics 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, ME-CFS, other

This review directly addresses mtDNA escape from dysfunctional mitochondria as a DAMP activating innate immune/inflammatory pathways (cGAS-STING, NLRP3), which mirrors the BLUE and PURPLE mechanistic streams of SAMHD1 haploinsufficiency, though the upstream trigger is ozone rather than dNTP pool expansion via SAMHD1 loss.
DOI: 10.3390/toxics14030248

Pathogenic role of mitochondrial DNA mutations in heart failure: clinical features, mechanisms, and therapeutic prospects (from Cardiology)
Mingyang Ni; Aijia Zheng; Hang Zheng; Wenqing Jia; Yuansheng Wang — Frontiers in Cardiovascular Medicine 2026
Score: 6/10 | Pathways: POLG-mtDNA, cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy, clinical-phenotype, other

This review directly addresses mtDNA mutation-driven innate immune activation (cGAS-STING, NLRP3), mitochondrial structural dysfunction (VDAC1, dynamics), oxidative stress, and metabolic reprogramming in cardiac disease — all core loops of the SAMHD1 interferonopathy mechanism — with cardiology phenotype relevance given the family's interferonopathy-driven mitochondrial cardiomyopathy risk, though SAMHD1 itself is not mentioned.
DOI: 10.3389/fcvm.2026.1781927

Lethal effects of a hyperactive dGTP triphosphohydrolase in E. coli. (from microbiology/biochemistry)
Bhawsinghka Niketa; Glenn Katie F; Klemm Bradley P; Singh Deepa; Day Ryan C — 2026
Score: 5/10 | Pathways: dNTPase, POLG-mtDNA, other

This paper directly investigates the consequences of hyperactive dGTPase activity causing dGTP depletion and chromosomal disruption in E. coli, which is mechanistically inverse but conceptually adjacent to the SAMHD1 haploinsufficiency disease model where reduced dNTPase activity causes dGTP pool expansion — both scenarios underscore the critical importance of precise dNTP pool regulation, particularly dGTP, for genomic integrity and cell viability.
DOI: 10.1093/genetics/iyag139

Mitochondrial Metabolic Reprogramming in Colorectal Cancer-Associated Fibroblasts: An Up-to-Date Review. (from Oncology/Cancer Biology)
Li Ying; Chanda Dipanjan; Jeon Seong-Woo; Jeon Jae-Han; Kim Min-Ji — 2026
Score: 5/10 | Pathways: cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy, mTOR-lysosomal, other

This review covers CAF mitochondrial reprogramming in CRC and explicitly discusses mtDNA-mediated cGAS-STING signaling, AMPK-PGC-1α, mitophagy/fission-fusion dynamics, and ROS-NF-κB pathways that are directly mechanistically relevant to the SAMHD1 interferonopathy model, but the context is tumor-stroma crosstalk rather than germline interferonopathy or dNTPase haploinsufficiency, making the connection indirect.
DOI: 10.3390/cancers18111786

Manganese Vacancy-Engineered Prussian Blue Triggers Pyroptosis-Driven Innate Immunity for Second Near-Infrared Region Photoimmunotherapy. (from Oncology/Nanomedicine)
Wang Xiaorui; Li Runtao; Wang Ye; Li Yunpeng; Liu Liren — 2026
Score: 5/10 | Pathways: cGAS-STING, NLRP3, POLG-mtDNA, other

This paper demonstrates the mechanistic link between ROS-induced gasdermin E-mediated pyroptosis, cytosolic mtDNA release, and cGAS-STING activation—pathways directly relevant to the SAMHD1 disease model—but in an engineered oncology/photoimmunotherapy context that is mechanistically informative but clinically distant from haploinsufficiency-driven interferonopathy.
DOI: 10.1021/acsnano.6c05567

Barrier-to-autointegration factor protects against the cGAS-STING response to chromatin bridges. (from Cell biology / mitosis)
Chastant Laura; Normandin Karine; El-Mortada Firas; Servant Marc J; Archambault * — 2026
Score: 5/10* | Pathways: cGAS-STING, other

This paper characterizes BAF (Barrier-to-Autointegration Factor) as a suppressor of cGAS-STING activation via chromatin bridge stabilization—a nuclear/mitotic mechanism distinct from the SAMHD1/VDAC1/mtDNA route, but confirming that cGAS-STING can be potently activated by aberrant chromatin structures and that IRF3-dependent proinflammatory transcription results; relevant as contextual mechanistic background for the BLUE stream but does not touch SAMHD1, mitochondria, dNTP pools, or any family phenotype directly.
DOI: 10.1371/journal.pgen.1012191

Acacetin ameliorates MASLD by inhibiting the Notch1 pathway in hepatocytes and reprogramming macrophage polarization via Keap1-Nrf2-mediated restraint of ferroptosis. (from Hepatology)
Xu Jun; Ying Huiya; Wang Yixiao; Zeng Yuan; Zhao Qian — 2026
Score: 5/10 | Pathways: cGAS-STING, VDAC1, IRF7-metabolic, NLRP3, treatment-target, other

The paper directly demonstrates that mitochondrial injury drives mtDNA release activating cGAS-STING in macrophages (a core BLUE-stream pathway in the disease model), and documents hepatic steatosis/MASLD — a tracked family phenotype — but the mechanism is studied in a non-SAMHD1 context with no connection to dNTPase haploinsufficiency, making it an adjacent mechanistic parallel rather than a direct hit.
DOI: 10.1016/j.metabol.2026.156670

Mitochondrial OXPHOS restricts SARS-CoV-2 replication. (from virology/cell metabolism)
Soto Albrecht Yentli E; Morrow Ryan M; Kenney Devin; Olali Arnold Z; Wacquiez Al — 2026
Score: 5/10 | Pathways: POLG-mtDNA, ME-CFS, dNTPase, other

This paper demonstrates that mitochondrial OXPHOS suppresses SARS-CoV-2 replication via metabolic balance rather than innate immune differences, which is indirectly relevant because the SAMHD1 A565T haploinsufficiency causes mitochondrial dysfunction (via POLG stalling, perturbed dNTP pools, and OXPHOS impairment), potentially creating a permissive environment for enhanced SARS-CoV-2 replication and post-viral ME/CFS triggering in the proband, but the paper explicitly rules out innate immune pathway differences as the mechanism, limiting its direct relevance to the cGAS-STING/interferonopathy axis central to this disease.
DOI: 10.1126/sciadv.adz3081

Negative regulators antagonizing antitumor innate immune pathways in lung cancer immune evasion (from Oncology)
Fan Yang; Rui Liu; Li Liu; Aijie Zhang; Bo Li — Frontiers in Immunology 2026
Score: 5/10 | Pathways: cGAS-STING, JAK-STAT, IRF7-metabolic, other

This review covers cGAS-STING, type I interferon, and innate immune evasion mechanisms directly relevant to the SAMHD1 interferonopathy framework, including metabolic reprogramming and ubiquitin-mediated regulation, but the lung cancer focus and lack of SAMHD1, NLRP3, VDAC1, or mitophagy content limits direct applicability to the disease profile.
DOI: 10.3389/fimmu.2026.1842558

The human cytomegalovirus vMIA protein inhibits apoptosis and innate immune signaling in human Mueller cells. (from ophthalmology/virology)
M. M. Sauter; H. Noel; Curtis R. Brandt — Experimental eye research 2026
Score: 5/10 | Pathways: cGAS-STING, VDAC1, ME-CFS, other

The paper demonstrates viral modulation of the cGAS-STING pathway and mitochondrial apoptosis signaling via vMIA, which intersects with core BLUE-stream mechanisms (cGAS-STING, mitochondrial morphology/MAVS, VDAC1-adjacent apoptosis) relevant to SAMHD1 interferonopathy, but the retinal/ocular context and viral immunoevasion framing are tangential to the family's haploinsufficiency syndrome.
DOI: 10.1016/j.exer.2026.111009

JAK inhibition in PD-1 immunotherapy and tumor microenvironment (from Oncology/Immuno-oncology)
Ziyuan Liu; Jiaqi Liu; Hongyu Chu; Zhuming Lu; Shengshan Xu — Frontiers in Immunology 2026
Score: 5/10 | Pathways: JAK-STAT, treatment-target, other

This review covers JAK/STAT signaling and JAK inhibitors (baricitinib, ruxolitinib class) in the tumor microenvironment, which are directly relevant as treatment targets for the SAMHD1 interferonopathy (IFN-I → JAK-STAT1/2 → ISG15 → mitophagy block), but the paper's focus is on cancer immunotherapy resistance rather than the interferonopathy or mitochondrial mechanisms central to SAMHD1 haploinsufficiency, making it an indirect therapeutic connection.
DOI: 10.3389/fimmu.2026.1790936

Dysregulated dsRNA sensor signaling and viral infection during onset of pediatric autoimmune interferonopathy (from Pediatric rheumatology/myology)
MOREAU, T. R.; AQUINO, Y.; ZHU, Y. Y.; BONDET, V.; ALBERT-VEGA, C.; DONNADIEU, F — bioRxiv (preprint) 2026
Score: 5/10 | Pathways: JAK-STAT, AGS-spectrum, ME-CFS, cGAS-STING, clinical-phenotype, other

This paper demonstrates SARS-CoV-2 and RNA viral triggers driving dysregulated IFN-I/MDA5 signaling with myeloid ISG enrichment in pediatric autoimmune interferonopathy (JDM), which is mechanistically adjacent to the SAMHD1 haploinsufficiency model—particularly the viral trigger hypothesis (proband's adenovirus/SARS-CoV-2 onset), IFN-I loop amplification, and JAK-STAT pathway dysregulation—but does not address SAMHD1, cGAS-STING, VDAC1, mtDNA, or the specific dNTP-driven mechanism.
DOI: 10.64898/2026.05.27.728148

🟢 Low Relevance (Score 3–4)

Potential specialty bridges — skim titles

Emerging perspectives in proteostasis: bridging mechanisms and therapeutics for human diseases. (from cell biology / molecular pharmacology)
Borlepawar Ankush; Neu Marco; Ma Ziqi; Deshpande Anushka; Bühringer Hannah — 2026
Score: 4/10 | Pathways: mTOR-lysosomal, ISG15-mitophagy, NLRP3, other

This broad proteostasis review tangentially touches autophagy-mitophagy, ubiquitin-proteasome, and lysosomal pathways relevant to the ISG15-mitophagy block and NLRP3 inflammasome axes in the disease model, but contains no specific focus on SAMHD1, cGAS-STING, interferonopathy, or the core molecular players driving the convergent interferon-mitochondrial syndrome.
DOI: 10.1038/s41392-026-02714-4

Association Between Type I Interferonopathies and the Development of Cutaneous Sarcoidosis, Morphea, Lichen Planus and Granuloma Annulare: A Retrospective Cohort Study. (from Dermatology)
Block Brandon; Mehta Jaanvi; Soto-Canetti Gabriela; Tang Alice; Spingler Riley — 2026
Score: 4/10 | Pathways: JAK-STAT, AGS-spectrum, clinical-phenotype, other

This paper documents clinical associations between IFN-I-driven systemic diseases and specific autoimmune dermatoses (LP, morphea, CS, GA), confirming that chronic type I interferonopathy states predispose to these skin conditions, which is peripherally relevant as downstream phenotypic consequences of the same JAK-STAT/IFN-I axis central to SAMHD1 haploinsufficiency, but provides no mechanistic insight into cGAS-STING, NLRP3, VDAC1, or SAMHD1-specific pathways.
DOI: 10.1111/exd.70295

Coexisting ADAR and TSHB Mutations in an Infant With Retinal Detachment and Transient Cardiomyopathy. (from Neonatology/Pediatric Genetics)
Draidi Tamer; Khalil Mohammad; Kabaha Abed; Zuriqi Rafat; Masu'd Mohammad — 2026
Score: 4/10 | Pathways: AGS-spectrum, cGAS-STING, clinical-phenotype

This case documents ADAR-related AGS6, a type I interferonopathy sharing the AGS-spectrum with SAMHD1-related disease, but involves a different gene (ADAR), a distinct molecular mechanism (RNA editing failure rather than dNTPase/cGAS-STING), and the clinical novelty is the co-occurring TSHB mutation; the connection to SAMHD1 haploinsufficiency pathways is only via the broad interferonopathy/AGS diagnostic category.
DOI: 10.1155/crie/5534847

NF-κB signaling in osteoarthritis: integrating mechanical stress, innate immunity, and cartilage degeneration (from Rheumatology/Orthopedics)
Peng Wan; Yimin Zheng — Frontiers in Immunology 2026
Score: 4/10 | Pathways: NLRP3, VDAC1, POLG-mtDNA, urate-NLRP3, other

This OA review touches on NF-κB as a hub integrating mitochondrial dysfunction-associated DNA sensing (obliquely referencing cGAS-STING/NLRP3 pathways) and DAMP-driven innate immune circuits that overlap mechanistically with the SAMHD1 interferonopathy framework, but remains disease-context-specific to cartilage degeneration with no direct relevance to SAMHD1, type I interferon, ISG15-mitophagy, or the family phenotype cluster.
DOI: 10.3389/fimmu.2026.1842443

Identification and diagnostic potential of pyroptosis-related genes in endometriosis: A novel bioinformatics analysis and validation. (from Gynecology/reproductive medicine)
Wang Li; Teng Piaopiao; Chen Jiawen; Ding Caiyun; Luo Xianchen — 2026
Score: 3/10 | Pathways: NLRP3, clinical-phenotype, other

This paper investigates pyroptosis-related genes in endometriosis with some NLRP3/inflammasome relevance and touches on a gynecologic inflammatory condition, but the identified gene signatures (KIF13B, BAG6, MYO5A, HEATR2) have no direct connection to SAMHD1 pathways, cGAS-STING, or the core interferon-mitochondrial mechanism, making this only tangentially relevant via the shared pyroptosis/inflammasome biology and the family's endometrial carcinoma phenotype.
DOI: 10.1371/journal.pone.0350751

A designed peptide disrupting viral protease cleavage restores cGAS-DNA phase separation and type I interferon responses. (from veterinary virology / antiviral therapeutics)
Yin Hongyan; Zhao Zhenchao; Wang Haiwei; Li Xin — 2026
Score: 3/10 | Pathways: cGAS-STING, NLRP3, other

While the paper involves cGAS-DNA phase separation and innate immune signaling (cGAS-STING pathway) relevant to the disease mechanism, the context is entirely viral (SVV 3C protease in porcine systems) and addresses antiviral peptide inhibition rather than constitutive interferonopathy or SAMHD1-related pathology, making the connection tangential at best.
DOI: 10.1371/journal.ppat.1014291

Mechanisms by Which Exercise Delays Brain Aging Through Regulation of the Mitochondrial Quality Control System. (from Exercise physiology / sports medicine / neuroscience)
Zhu Xinyi; Shi Lei; Dong Yahong; Sun Yingjie; Jin Qiguan — 2026
Score: 3/10 | Pathways: mTOR-lysosomal, ISG15-mitophagy, other

This review covers mitochondrial quality control (biogenesis via PGC-1α/AMPK/SIRT1, mitophagy via PINK1/Parkin/mTOR, dynamics via Drp1) which are downstream components of the RED and PURPLE streams, but the paper is entirely focused on exercise as an intervention for brain aging with no connection to SAMHD1, interferonopathy, cGAS-STING, NLRP3, or the specific pathological context of this family.
DOI: 10.3390/biology15110854

The Role of MicroRNAs Carried by Extracellular Vesicles in Tumorigenesis Through Reprogramming the Mitochondrial Information Processing System. (from Oncology/Cancer Biology)
Ghosh-Mitra Arpita; Patel Mansi; Das Samarjit — 2026
Score: 3/10 | Pathways: VDAC1, POLG-mtDNA, mTOR-lysosomal, other

This review covers EV-miRNA reprogramming of mitochondrial dynamics, fission/fusion, and intrinsic apoptosis in tumorigenesis, touching peripherally on mitochondrial dysfunction and immune regulation relevant to the disease mechanism, but does not address SAMHD1, cGAS-STING, NLRP3, ISG15, interferonopathy, or any direct pathway component with meaningful specificity.
DOI: 10.3390/ijms27115112

Metabolic reprogramming in fibrosis-related diseases: underlying mechanisms and therapeutics. (from hepatology-nephrology-cardiology (fibrosis))
Feng Yourong; Zhang Xudong; Wang Xin Joy; Chen Chen — 2026
Score: 3/10 | Pathways: IRF7-metabolic, mTOR-lysosomal, other

This review covers metabolic reprogramming in fibrosis (Warburg effect, glycolysis, lipid metabolism) with some overlap in downstream metabolic consequences of mitochondrial dysfunction and NF-kB/inflammatory signaling, but does not address cGAS-STING, NLRP3, SAMHD1, interferonopathy, or the core pathways driving the A565T syndrome, making the connection tangential.
DOI: 10.1186/s43556-026-00490-9

Clonal lineage tracing of innate immune cells in human cancer. (from Oncology/Tumor Immunology)
Vincent Liu; Katalin D. Sandor; Patrick K. Yan; Zhuang Miao; Yajie Yin — Cancer cell 2026
Score: 3/10 | Pathways: POLG-mtDNA, other

While this paper uses somatic mtDNA mutations as lineage tracing barcodes to study innate immune clonal dynamics in the tumor microenvironment, its use of mtDNA is purely as a neutral genetic marker rather than addressing any mechanistic pathway relevant to SAMHD1 haploinsufficiency, cGAS-STING, NLRP3, or mitochondrial dysfunction in the disease context.
DOI: 10.1016/j.ccell.2026.05.006

Effect of nanobody-STING agonists on the tumor microenvironment and adoptive cell therapy for solid tumors. (from Oncology/Immunotherapy)
Neil C. Chada; Alex Lee; Hailey Jane Frank; Dawn K. Oh; Hannah Ki — Journal of Clinical Oncology 2026
Score: 3/10 | Pathways: cGAS-STING, treatment-target, other

This paper involves STING pathway activation but purely in the context of tumor immunotherapy (adoptive cell therapy for solid tumors), with no mechanistic connection to SAMHD1 haploinsufficiency, interferonopathy, mitochondrial dysfunction, or the family phenotype constellation; the STING agonism here is an oncologic tool rather than an exploration of pathological constitutive cGAS-STING activation.
DOI: 10.1200/jco.2026.44.16_suppl.e14601

Abstract LB415: Nanobody:STING agonists reprogram the tumor microenvironment and improve adoptive cell therapy for solid tumors (from Oncology/Immuno-oncology)
Neil C. Chada; Alex Lee; Hailey Jane Frank; Dawn K. Oh; Hannah Ki — Cancer Research 2026
Score: 3/10 | Pathways: cGAS-STING, treatment-target, other

While this paper involves STING pathway activation, it focuses on a nanobody-based tumor immunotherapy platform for solid tumors rather than any aspect of SAMHD1 haploinsufficiency, interferonopathy, or the downstream mitochondrial/inflammasome mechanisms relevant to the disease profile; STING is used here as a pharmacological target to enhance adoptive cell therapy, not in the context of constitutive cGAS-STING activation from mtDNA escape or SAMHD1 dysfunction.
DOI: 10.1158/1538-7445.am2026-lb415

Pathway Coverage This Week

other: 36 papers
cGAS-STING: 30 papers
NLRP3: 23 papers
POLG-mtDNA: 23 papers
VDAC1: 20 papers
treatment-target: 16 papers
ISG15-mitophagy: 15 papers
ME-CFS: 12 papers
JAK-STAT: 7 papers
clinical-phenotype: 6 papers
mTOR-lysosomal: 6 papers
dNTPase: 5 papers
AGS-spectrum: 4 papers
IRF7-metabolic: 3 papers
pregnancy-fetal: 1 papers
urate-NLRP3: 1 papers

June 7, 2026
in Weekly Digest, treatment-target, cGAS-STING, POLG-mtDNA, NLRP3
9 min read

SAMHD1 Research Digest — 2026-06-07

Generated by samhd1_monitor | Model: claude-sonnet-4-6

Summary: 21 papers evaluated | 9 high-relevance (≥7) | 6 medium (5–6) | 6 low (3–4) | 0 scored <3

🔴 High Relevance (Score 7–10)

Added to Zotero automatically

Mitochondrial DNA release and inflammation in mitochondrial disease pathogenesis. (from Mitochondrial disease / Genetics)
Szabo Marton; Lagos Daniel; Cross Emily; Collier Jack J; Horvath Rita — 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, NLRP3, POLG-mtDNA, ISG15-mitophagy, JAK-STAT, AGS-spectrum, ME-CFS, treatment-target, clinical-phenotype

This review directly covers the mechanistic chain central to SAMHD1 A565T pathogenesis—mtDNA release via mitochondrial membrane integrity loss (VDAC1), cGAS-STING activation, type I interferon/JAK-STAT signaling, and NLRP3 inflammasome engagement in primary mitochondrial diseases—and discusses therapeutic implications including cGAS-STING and NLRP3 inhibitors, making it highly relevant to all four mechanistic streams (PURPLE, BLUE, RED, GOLD) of the disease model.
DOI: 10.1093/brain/awag037

VDAC1 mediates LPS-induced T cell inflammation via mtDNA release and cGAS-STING activation. (from Critical care / sepsis immunology)
Yuqian Ren; Zhu Guangyao; Yucai Zhang; Yun Cui; Jie Gu — 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, NLRP3, treatment-target, ME-CFS

This paper directly demonstrates the VDAC1 oligomerization → mtDNA cytosolic release → cGAS-STING-TBK1 activation axis (the BLUE stream) in primary T cells, validates VBIT-12 as a pharmacological inhibitor of this pathway, and reports IL-18 elevation consistent with NLRP3 co-activation, making it highly mechanistically relevant to SAMHD1 haploinsufficiency pathophysiology where SAMHD1/VDAC1 interaction loss is proposed to drive the same cascade.
DOI: 10.1016/j.cellsig.2026.112642

Fingolimod increases cellular resistance to HIV-1 infection and limits viral reservoir size in peripheral CD4+ T-cells. (from Virology/HIV medicine)
Moraga Elisa; Climent Núria; Sánchez-Molina Alejandro; Vicens-Artés Sònia; Malen — 2026
Score: 7/10 | Pathways: dNTPase, treatment-target, ME-CFS, other

This paper directly demonstrates that SAMHD1 phosphorylation inhibition (via fingolimod) enhances dNTPase activity to restrict viral replication, providing mechanistic insight into how modulating SAMHD1 activity state — directly relevant to the haploinsufficiency context — affects dNTP pool dynamics and viral restriction, with fingolimod as a potential treatment modulator of the same SAMHD1 activity axis central to the disease mechanism.
DOI: 10.1371/journal.ppat.1014266

ALA-PDT Induces Apoptosis in HPV-transformed Cells through mtDNA Release-Mediated Activation of the cGAS-STING Pathway. (from Dermatology/photodynamic therapy)
Lei Shuangyi; Xu Rui; Deng Yuan; Feng Sining; Chen Yu — 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, VDAC1, treatment-target

This paper directly demonstrates the mechanistic sequence of mtDNA cytosolic release → cGAS-STING activation → apoptosis (confirmed by ρ0 depletion experiments), which is the core BLUE stream of the SAMHD1 haploinsufficiency mechanism, and pharmacological STING inhibition as a therapeutic target closely parallels the cGAS/STING inhibitor interventions (e.g., IMSB301) relevant to this disease.
DOI: 10.1016/j.pdpdt.2026.105534

Expanding roles of cGAS-STING signaling in neuroinflammation. (from Neurology/Neuroscience)
Feng Weixi; Aikedan Abulimiti; Sinha Subhash C; Gan Li — 2026
Score: 7/10 | Pathways: cGAS-STING, JAK-STAT, IRF7-metabolic, AGS-spectrum, ME-CFS, treatment-target

This review directly covers the cGAS-STING pathway (BLUE stream core mechanism) in neuroinflammation including canonical IFN-I induction, noncanonical nuclear roles, glial activation, blood-brain barrier integrity, and pharmacological inhibitors targeting cGAS/STING—all highly relevant to the SAMHD1 A565T interferonopathy mechanism where VDAC1-mediated cytosolic mtDNA fragments activate cGAS→cGAMP→STING→IRF3→IFN-I, and to the neurological phenotypes (AuDHD, ME/CFS, potential neurodegeneration) in the proband and family.
DOI: 10.1172/jci204550

Autoinflammatory syndromes of STING and TREX1 dysfunction. (from rare disease / genetics)
Park Debby J; Jones Kate M; Anderson Jessica B; Finck Amanda V; Miner Jonathan J — 2026
Score: 7/10 | Pathways: cGAS-STING, AGS-spectrum, dNTPase, treatment-target, clinical-phenotype

This review directly covers the cGAS-STING axis and its negative regulation by DNA-degrading enzymes (TREX1 paralleling SAMHD1's dNTPase role), STING gain-of-function vasculopathy, Aicardi-Goutières spectrum interferonopathies, and first-in-class small molecule therapeutics targeting this pathway—all directly mechanistically relevant to SAMHD1 haploinsufficiency-driven IFN-I overactivation via the BLUE stream (VDAC1→cGAS→STING→IRF3), though SAMHD1 itself is not discussed.
DOI: 10.1172/jci204549

Aspartate deficiency amplifies cGAS-STING signaling in antitumor immunity. (from Oncology/tumor immunology)
Liao Yuheng; Wang Hanze; Liu Hengxin; Chen Xi; Sun Renqiang — 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, JAK-STAT, dNTPase, treatment-target

This paper directly illuminates a mechanistic link between nucleotide pool imbalance (aspartate/pyrimidine depletion causing mtDNA replication stress and DSBs → cytosolic mtDNA release → cGAS-STING → IRF3 → type I IFN amplification via ZBP1 feedback loop) that mirrors the SAMHD1 haploinsufficiency mechanism where dNTP pool expansion (especially dGTP) perturbs mtDNA replication via POLG stalling and drives cGAS-STING-mediated interferonopathy — the novel ZBP1/RIPK1/3 positive feedback loop sustaining IRF3 phosphorylation is a clinically important amplification mechanism not previously mapped in the SAMHD1 disease model.
DOI: 10.1172/jci199716

Fueling the fire: aspartate deficiency primes and fuels STING activation. (from Oncology/tumor immunology)
Jiang Haitao; Wang Wenyan; Fu Yang-Xin — 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, dNTPase, ME-CFS, treatment-target

This paper directly addresses cGAS-STING pathway activation via mtDNA stress driven by nucleotide pool disruption (aspartate deficiency → pyrimidine depletion → mtDNA stress), which is mechanistically parallel to SAMHD1 haploinsufficiency causing dNTP pool imbalance → mtDNA stress → cGAS-STING activation, and introduces ZBP1/RIPK1/3 as a feed-forward amplifier of STING signaling relevant to understanding why interferonopathy is self-sustaining in this family.
DOI: 10.1172/jci206431

Mitochondrial protein COXFA4L3 (C15ORF48) confers resistance to DNA-damaging anticancer agents by repressing mitochondrial DNA damage responses. (from Oncology/Cancer Biology)
Takakura Yuki; Kawamura Seika; Hashiguchi Yui; Yamanaka Manami; Kurihara Yasuyuk — 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, VDAC1, treatment-target

This paper directly demonstrates the mtDNA damage → cytosolic mtDNA release via mPTP → cGAS-STING activation axis that is central to the BLUE stream of SAMHD1 haploinsufficiency pathophysiology, specifically showing that mtDNA damage and mPTP-mediated cytosolic release drives cGAS-STING-dependent cell death, with COXFA4L3 as a novel repressor of this pathway—directly relevant to understanding how SAMHD1's interaction with VDAC1/mPTP components leads to chronic IFN-I signaling.
DOI: 10.1038/s41598-026-54548-3

🟡 Medium Relevance (Score 5–6)

Review and add to Zotero manually if warranted

GSDME-Mediated Pyroptosis and the mtDNA-cGAS-STING Pathway Drive Deoxynivalenol-Induced Porcine Intestinal Inflammatory Injury. (from Veterinary/Food toxicology and gastroenterology)
Zhou Fenfen; Li Jie; Li Mingxuan; Guo Chongwen; Mao Xiaoxiao — 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, other

This paper directly demonstrates the mechanistic sequence of mitochondrial membrane permeabilization → cytosolic mtDNA release → cGAS-STING activation driving chronic intestinal inflammation, which mirrors the BLUE pathway (VDAC1 macropore → mtDNA escape → cGAS-STING) central to SAMHD1 haploinsufficiency, though the trigger (GSDME/caspase-3 pyroptosis from mycotoxin) is distinct from SAMHD1-driven VDAC1 dysregulation.
DOI: 10.1021/acs.jafc.6c01535

Interstitial lung disease and the STING pathway. (from Pulmonology)
Velu Prasad Palani; Zhu Gaofeng; Mackenzie Karen J — 2026
Score: 6/10 | Pathways: cGAS-STING, JAK-STAT, IRF7-metabolic, AGS-spectrum, treatment-target, clinical-phenotype

This review directly covers the STING pathway in ILD, including SAVI and COPA syndrome which are type I interferonopathies mechanistically overlapping with SAMHD1 haploinsufficiency via cGAS-STING-IRF3 signaling, and discusses STING-targeted therapeutics relevant to Loop A of the disease mechanism, though it does not address SAMHD1, mtDNA, VDAC1, or the specific family phenotype.
DOI: 10.1172/jci204544

An Engineered Microbial Nanohybrid for Enhanced Ferroptosis Immunotherapy via Hypoxia-Responsive Hydrogen Sulfide Generation and Mitophagy Inhibition. (from Oncology/Nanomedicine)
Li Yuewei; Xu Shujing; Wang Guocheng; Song Zhangzhi; Zhang Shuqi — 2026
Score: 5/10 | Pathways: cGAS-STING, POLG-mtDNA, ISG15-mitophagy, BIK-cancer, treatment-target

The paper demonstrates mechanistic relevance to the disease model—specifically cytosolic mtDNA accumulation activating cGAS-STING and deliberate mitophagy inhibition (Mdivi-1) to sustain that signal—but is framed entirely as an oncology ferroptosis immunotherapy strategy in a murine mammary carcinoma model, with no connection to SAMHD1, haploinsufficiency, or the interferonopathy syndrome; the mechanistic insights into mtDNA–cGAS–STING amplification via mitophagy blockade are indirectly informative for understanding the RED/BLUE loop intersection in the disease mechanism.
DOI: 10.1021/acsnano.6c06383

Mitophagy in cisplatin-induced kidney injury: regulatory mechanisms and therapeutic targets. (from nephrology/oncology)
Yuan Cheng; Jiang Jinzhou; Ji Jinxing; Ni Lihua — 2026
Score: 5/10 | Pathways: NLRP3, ISG15-mitophagy, POLG-mtDNA, mTOR-lysosomal, other

This review covers PINK1/Parkin-dependent mitophagy, pyroptosis/NLRP3 inflammasome, and mitochondrial quality control mechanisms that are directly relevant to the RED-stream ISGylation-mediated mitophagy block and NLRP3 activation central to the disease model, but the cisplatin-AKI context is clinically unrelated and the paper does not address cGAS-STING, SAMHD1, or type I interferonopathy.
DOI: 10.1080/07853890.2026.2672141

Mitochondrial dysfunction in neurodegenerative disorders: mechanisms and therapeutic advances. (from Neurology/neurodegeneration)
Tong Yan; He Jing Na; Zhou Linbin; Zhang Jiaxin; Ho Bo Man — 2026
Score: 5/10 | Pathways: POLG-mtDNA, ISG15-mitophagy, VDAC1, mTOR-lysosomal, treatment-target, other

This review covers mitochondrial dynamics, quality control (mitophagy), oxidative phosphorylation defects, and mtDNA integrity—all mechanistically central to the PURPLE and RED streams of the SAMHD1 haploinsufficiency model—but does not engage with cGAS-STING, interferonopathy, NLRP3, or SAMHD1 itself, making it background context rather than directly actionable evidence.
DOI: 10.1186/s43556-026-00480-x

PRKN Ser131 phosphorylation promotes cigarette smoke-induced mitophagy impairment and epithelial cell senescence via MKK3/p38 MAPK activation: An in vitro and in vivo study. (from Pulmonology/COPD)
Hu Yajie; Liu Jianyu; Zhang Mengyu; Qu Jiajia; Hao Wenqiang — 2026
Score: 5/10 | Pathways: ISG15-mitophagy, other

This paper directly investigates Parkin (PRKN)/PINK1-dependent mitophagy impairment via a phosphorylation-mediated block, which is directly relevant to the RED stream where ISGylation of PINK1/Parkin blocks mitophagy, but the mechanism here is MKK3/p38 MAPK-driven rather than ISG15/interferonopathy-driven, making it an adjacent mechanistic parallel rather than a core pathway contribution.
DOI: 10.18332/tid/218816

🟢 Low Relevance (Score 3–4)

Potential specialty bridges — skim titles

Metabolic dysfunction-associated steatotic liver disease: pathogenesis and novel treatment options. (from hepatology)
Ren Ruizhe; Liang Xiao; Wei Xiyang — 2026
Score: 4/10 | Pathways: NLRP3, IRF7-metabolic, mTOR-lysosomal, urate-NLRP3, other

MASLD review touches on mitochondrial dysfunction, inflammasome/NLRP3 activation, and hepatic steatosis which are family phenotype-adjacent (hepatic steatosis listed explicitly, cholecystectomy clustering), but does not engage cGAS-STING, SAMHD1, ISG15, VDAC1, or interferonopathy mechanisms that would make it mechanistically relevant to the disease profile.
DOI: 10.1186/s43556-026-00486-5

A genomic structural equation modelling analysis of the shared genetic architecture of the aging spine. (from Orthopedic genetics / musculoskeletal genomics)
Chen Jianquan; Zhong Xingjie; Li Liping; Feng Peiyun; Duan Xiuping — 2026
Score: 3/10 | Pathways: dNTPase, other

SAMHD1 appears as a GWAS/TWAS susceptibility gene for aging spine traits (lumbar spinal stenosis, disc degeneration, sciatica) via genomic stability pathways, but the paper treats it purely as a statistical genomic signal without any mechanistic investigation of dNTPase function, interferonopathy, or the SAMHD1 p.A565T variant, making it tangentially relevant at best.
DOI: 10.1007/s00586-026-10039-7

Highly Efficient Lentiviral Transduction of Human iPSC-Derived Microglia and Macrophages (from Neuroscience/cell biology methods)
Goberdhan Srilakshmi; Czubala Magdalena; Thomas Sophie; Taylor Philip; Connor-Ro — 2026
Score: 3/10 | Pathways: dNTPase, other

This paper mentions SAMHD1 only as a lentiviral restriction factor in myeloid cells that is removed via VPX to improve transduction efficiency in iPSC-derived microglia, providing no mechanistic insight into SAMHD1 haploinsufficiency, dNTPase function, or any of the core interferon-mitochondrial pathways relevant to the A565T variant.
DOI: 10.64898/2026.05.23.727402

Insights into the therapeutic strategies for aging and aging-associated diseases. (from Geroscience/longevity medicine)
Dong Ruifang; Wu Qiming; Kan Juntao; Fu Caili; Sorrentino Vincenzo — 2026
Score: 3/10 | Pathways: mTOR-lysosomal, NLRP3, ISG15-mitophagy, other

This broad aging review touches on mitochondrial impairment, cellular senescence, autophagy (rapamycin/mTOR), and SASP—mechanisms that partially overlap with the SAMHD1 interferonopathy-mitochondrial cascade—but contains no direct engagement with cGAS-STING, NLRP3 inflammasome, VDAC1, ISG15, or SAMHD1, making it only tangentially relevant as background context.
DOI: 10.1038/s41392-026-02662-z

Nanozymes for Bone Regeneration: Mechanistic Insights into Immune and Metabolic Microenvironment Modulation. (from Biomaterials/Orthopedic tissue engineering)
Wang Yue; Song Meiyuan; Chen Shumeng; He Yang; Chen Shuxuan — 2026
Score: 3/10 | Pathways: NLRP3, other

This nanozyme review touches on NLRP3/NF-κB suppression and mitochondrial function restoration in the context of bone regeneration, which are peripheral overlaps with the disease mechanism, but the paper is fundamentally about biomaterial engineering for orthopedic repair with no connection to SAMHD1, interferonopathy, dNTP biology, or the family phenotype.
DOI: 10.2147/ijn.s607165

The homozygous founder Psmb8 variant of Nakajo-Nishimura syndrome/proteasome-associated autoinflammatory syndrome causes panniculitis-associated lipoatrophy and a shortened lifespan in mice. (from Rare disease / autoinflammatory immunology)
Hara Tomoyuki; Kinoshita Akira; Hamazaki Jun; Hemmi Hiroaki; Kato Takashi — 2026
Score: 3/10 | Pathways: NLRP3, JAK-STAT, AGS-spectrum, clinical-phenotype, other

This paper describes a proteasome-dysfunction autoinflammatory syndrome (NNS/PRAAS) driven by PSMB8 variants, which causes type I interferonopathy features (periodic fever, lipoatrophy, cytokine activation) via a proteasome-ubiquitin pathway mechanistically distinct from the SAMHD1/cGAS-STING/NLRP3 axes central to SAMHD1 A565T haploinsufficiency, making it a tangential interferonopathy model with limited direct pathway overlap.
DOI: 10.1038/s41598-026-51190-x

Pathway Coverage This Week

treatment-target: 12 papers
cGAS-STING: 11 papers
other: 11 papers
POLG-mtDNA: 9 papers
NLRP3: 8 papers
VDAC1: 6 papers
ISG15-mitophagy: 6 papers
dNTPase: 6 papers
JAK-STAT: 5 papers
AGS-spectrum: 5 papers
ME-CFS: 5 papers
clinical-phenotype: 4 papers
mTOR-lysosomal: 4 papers
IRF7-metabolic: 3 papers
BIK-cancer: 1 papers
urate-NLRP3: 1 papers

May 31, 2026
in Weekly Digest, NLRP3, cGAS-STING, POLG-mtDNA, VDAC1
19 min read

SAMHD1 Research Digest — 2026-05-31

Generated by samhd1_monitor | Model: claude-sonnet-4-6

Summary: 44 papers evaluated | 24 high-relevance (≥7) | 9 medium (5–6) | 11 low (3–4) | 0 scored <3

🔴 High Relevance (Score 7–10)

Added to Zotero automatically

Rab26 Mitigates Ferroptosis in Airway Epithelium Induced by Cigarette Smoke Through Suppression of VDAC1 Oligomerization-Mediated cGAS-STING Activation. (from Pulmonology/COPD)
Tian Xin; Zhang Wen; You Zaichun; Mao Yang; Huang Qiuhong — 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, treatment-target

This paper directly demonstrates the VDAC1 oligomerization → cytosolic mtDNA release → cGAS-STING activation axis (the BLUE stream of the SAMHD1 haploinsufficiency mechanism), providing novel molecular detail on how VDAC1 macropore formation drives cGAS-STING hyperactivation, and validates STING inhibition as a pharmacological rescue—highly relevant to the SAMHD1/VDAC1 interaction loss mechanism in this disease.
DOI: 10.1016/j.freeradbiomed.2026.05.315

Glutathione peroxidase 3 preserves hepatocyte mitochondrial quality control to enhance macrophage pro-regenerative phenotype during liver regeneration. (from Hepatology)
Wang Yuechen; Xu Jian; Zhu Zeyu; Zhang Ye; Hu Haoran — 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, ISG15-mitophagy, JAK-STAT, POLG-mtDNA, treatment-target

This paper directly demonstrates the mechanistic axis of VDAC1 oligomerization → mtDNA release → cGAS-STING activation → type I interferon overproduction that constitutes the BLUE stream of the SAMHD1 A565T pathomechanism, with the added finding that STING hyperactivation suppresses regenerative signaling — providing a novel hepatology context and a GPX3-based therapeutic angle relevant to the family's hepatic phenotype (cholecystectomy clustering, hepatic steatosis).
DOI: 10.1002/ctm2.70695

Pathogenic variants in the autophagy-tethering factor EPG5 drive neurodegeneration through mitochondrial dysfunction and innate immune activation. (from Neurology/rare disease (Vici syndrome/EPG5))
Singh Kritarth; Dafsari Hormos Salimi; Gillham Olivia; Chi Haoyu; Mandzhukova Iv — 2026
Score: 8/10 | Pathways: cGAS-STING, ISG15-mitophagy, VDAC1, POLG-mtDNA, mTOR-lysosomal, treatment-target

This paper directly demonstrates the mechanistic cascade central to the SAMHD1 A565T syndrome: impaired mitophagy → mitochondrial bioenergetic dysfunction → mtDNA release → cGAS-STING innate immune activation, with pharmacological rescue by mPTP or STING inhibition, precisely mirroring the BLUE and RED pathway loops in the disease mechanism, and providing therapeutic target validation highly relevant to this interferonopathy.
DOI: 10.1038/s41467-026-73538-7

Self-assembled nanoparticles from Xiexin Decoction attenuate ulcerative colitis by targeting VDAC1-Mediated NLRP3 inflammasome activation (from Nanomedicine/Traditional Chinese Medicine pharmacology)
Zheng Chu; Tong Yang; Ying Zhang; Qianru Zhu; Dawei Wang — Materials Today Bio 2026
Score: 8/10 | Pathways: VDAC1, NLRP3, cGAS-STING, POLG-mtDNA, treatment-target

This paper directly demonstrates that VDAC1 oligomerization drives cytosolic oxidized mtDNA release → NLRP3 inflammasome activation in macrophages, precisely the BLUE+PURPLE mechanistic axis of SAMHD1 haploinsufficiency, and identifies berberine as a functional VDAC1 inhibitor that blocks this pathway—providing a directly actionable treatment target for the convergent interferon-mitochondrial syndrome described.
DOI: 10.1016/j.mtbio.2026.103078

TH5487 specifically targets NLRP3 in FCAS patients resistant to MCC950 (from chemical biology / rare autoinflammatory disease (FCAS))
Angela Lackner; Sofia I. Picucci; Wenjing Jiang; Janset Onyuru; Melissa Campos — Communications Biology 2026
Score: 8/10 | Pathways: NLRP3, POLG-mtDNA, cGAS-STING, treatment-target, ME-CFS

This paper directly addresses NLRP3 inflammasome regulation via oxidized mitochondrial DNA sensing (cryo-EM showing NLRP3-mtDNA association), introduces a novel druggable mechanism (hOGG1 inhibition via TH5487) effective where MCC950 fails, and notably reports that these inhibitors simultaneously reduce IL-1β while increasing type I interferon responses—directly relevant to the PURPLE stream (ox-mtDNA → NLRP3) and the convergent interferon-mitochondrial syndrome mechanism, with clear treatment implications for MCC950-resistant NLRP3 activation in this haploinsufficiency context.
DOI: 10.1038/s42003-026-10008-2

Oxidized mtDNA Contributes to Pulmonary Inflammation and Fibrosis in Bleomycin‐Induced Lung Injury (from Pulmonology/fibrosis)
Ye Mao; Xinyu Tian; Jiayuan Ai; Xiaoting Zhou; Yanghong Ni — MedComm 2026
Score: 8/10 | Pathways: cGAS-STING, NLRP3, POLG-mtDNA, treatment-target, other

This paper directly demonstrates that oxidized mtDNA (the exact molecular species generated by POLG stalling in the PURPLE pathway) activates both cGAS-STING and NLRP3 downstream to drive inflammation and fibrosis, with knockout mouse validation of both pathways — mechanistically mirroring the BLUE and GOLD/PURPLE loops central to the SAMHD1 A565T syndrome.
DOI: 10.1002/mco2.70664

Human Immunodeficiency Virus Type 2 Vpx-mediated Degradation of TASOR Activates Innate Immune Sensing of Nucleic Acids in Infected Cells. (from Virology/Retrovirology)
Hanson Heather M; Damkot Madeline R; Mansky Louis M — 2026
Score: 7/10 | Pathways: cGAS-STING, dNTPase, JAK-STAT, AGS-spectrum, ME-CFS

This paper directly demonstrates that SAMHD1 degradation by Vpx elevates dNTP levels and that a parallel Vpx function (TASOR/HUSH degradation) activates cGAS-STING and MAVS-mediated ISG induction in monocytic cells, providing mechanistic context for how SAMHD1 haploinsufficiency combined with viral triggers (e.g., adenovirus/SARS-CoV-2) could synergize to amplify the cGAS-STING-ISG axis central to the family's interferonopathy.
DOI: 10.1016/j.jmb.2026.169879

PLSCR3 Deficiency Triggers mtDNA-Driven cGAS-STING Activation to Potentiate Antitumor Immunity in Colorectal Cancer. (from Oncology (colorectal cancer immunotherapy))
Ling Limian; Wu Jingyu; Bao Lei; Liu Zhaohui; Deng Qun — 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, ISG15-mitophagy, JAK-STAT, BIK-cancer

This paper directly demonstrates that mitochondrial inner membrane disruption (via PLSCR3 deficiency) causes cytosolic mtDNA leakage activating cGAS-STING → IFNβ/CXCL10/ISG upregulation with functional immune consequences — precisely the BLUE stream mechanism in the SAMHD1 A565T model (VDAC1/mtDNA escape → cGAS → cGAMP → STING → IRF3 → IFN-I), and identifies PLSCR3 as a novel endogenous restraint on mtDNA release at the IMM, offering a new regulatory node adjacent to the disease mechanism.
DOI: 10.1155/humu/8545428

XBP1-mediated mitochondrial damage activates the mtDNA/STING/NLRP3 pathway to delay diabetic wound healing. (from Wound healing / diabetology)
Yi Min; Yan Wei; Tu Liying; Ni Tianyi; Zhang Qian — 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, POLG-mtDNA, treatment-target

This paper directly demonstrates the mtDNA → cGAS/STING → NLRP3 inflammatory cascade activated by mitochondrial damage in macrophages — the exact BLUE+PURPLE convergent pathway central to the SAMHD1 A565T mechanism — with XBP1 as an upstream trigger and pharmacological inhibition as a treatment strategy, providing mechanistic and therapeutic insight highly relevant to the disease model.
DOI: 10.1097/cm9.0000000000004113

Mitochondrial drivers of stem cell aging and inflammaging. (from Stem cell biology / geroscience)
Bautista Jhommara; López-Cortés Andrés — 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, POLG-mtDNA, ISG15-mitophagy, mTOR-lysosomal, ME-CFS, treatment-target, other

This review directly covers the core mechanistic streams of the SAMHD1 syndrome—mtDNA damage activating cGAS-STING, mitophagy failure (MQC erosion including fission-fusion and mitophagy), mtDAMP-driven inflammaging, and NAD⁺/sirtuin collapse—while also evaluating mitophagy enhancers and mitochondrial quality control as therapeutic targets, all highly relevant to the RED and BLUE pathway loops and the chronic inflammatory tone seen in ME/CFS and interferonopathy contexts, though SAMHD1 is not mentioned.
DOI: 10.1038/s41514-026-00422-5

Mitochondrial flagella-like extensions (MitoFLARE) dysfunction triggers STING-mediated immune dysregulation in sepsis. (from critical care / sepsis biology)
Hong Weilong; Ma Ruiyan; Long Shiyun; Song Rui; Ren Shuang — 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, other

This paper directly describes the mechanistic pathway from mitochondrial outer membrane rupture → cytosolic mtDNA release → cGAS-STING activation → inflammatory storm, which mirrors the BLUE stream of the SAMHD1 haploinsufficiency mechanism (VDAC1 macropore → mtDNA escape → cGAS-STING → IFN-I), and introduces novel intermediaries (MICOS-SAM complex disruption, mitoFLARE nanotube collapse, ER-mitochondrial contacts) that could explain how SAMHD1 loss of VDAC1 interaction accelerates outer membrane rupture and chronically activates cGAS-STING in a non-sepsis context.
DOI: 10.1038/s41467-026-73523-0

Mitochondrial Regulation of the NLRP3 Inflammasome in Diabetic Kidney Disease: From Mechanisms to Therapeutic Strategies (from Nephrology/Diabetology)
Xiangyun Chen; Zhenyu Wu; Kaiyan Yu; Juan Zhang; Hongjie Di — International Journal of Molecular Sciences 2026
Score: 7/10 | Pathways: NLRP3, POLG-mtDNA, VDAC1, urate-NLRP3, treatment-target

This review directly addresses the mitochondria–NLRP3 inflammasome axis including ox-mtDNA and mtROS as NLRP3 activators, which maps precisely onto the PURPLE and GOLD streams of the SAMHD1 A565T mechanism (POLG stalling → ox-mtDNA → NLRP3; urate-NLRP3), and evaluates therapeutic targeting strategies applicable to the family's inflammasome-driven pathology.
DOI: 10.3390/ijms27114819

Mitochondrial DNA regulation of hepatic ischemia-reperfusion injury and intervention strategies (from hepatology/transplant surgery)
Ruotong Shen; Peng An; Meng Chen; Ping Lu; Jingjing Yang — Journal of Translational Medicine 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, ISG15-mitophagy, treatment-target

This paper directly covers the core mechanistic triad—mtDNA escape → cGAS-STING activation → NLRP3 inflammasome/pyroptosis—plus mitochondrial quality control failure (mitophagy/fusion-fission/MDVs) that mirrors the PURPLE and BLUE loops in the SAMHD1 interferonopathy model, with explicit discussion of VDAC-mediated permeability, oxidized mtDNA as DAMP, and therapeutic intervention at each node (cGAS-STING inhibition, NLRP3 inhibition), making it highly mechanistically relevant even though the clinical context is hepatic IRI rather than SAMHD1 haploinsufficiency.
DOI: 10.1186/s12967-026-08155-5

Mitochondrial Dysfunction in the Inflammatory Process of Neurodegenerative Diseases (from Neurology/neurodegeneration)
Salvatore Nesci — Biomedicines 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, treatment-target, other

This review directly covers the mitochondrial dysfunction → oxidized mtDNA → cGAS-STING and NLRP3 inflammasome feed-forward loops that constitute the PURPLE and BLUE mechanistic streams of SAMHD1 haploinsufficiency, including respiratory supercomplex ROS generation, mtDNA damage-associated molecular pattern release, and therapeutic nodes targeting electron transport chain and mtDNA-sensing pathways, making it highly mechanistically relevant even without mentioning SAMHD1 itself.
DOI: 10.3390/biomedicines14030682

Mitochondrial Dysfunction in Acute Kidney Injury: Intersections Between Chemotherapy and Novel Cancer Immunotherapies (from Nephrology/Oncology)
Zaroon Zaroon; Carlotta D'Ambrosio; Filomena de Nigris — Biomolecules 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, treatment-target, other

This review directly covers cGAS-STING activation by mtDNA DAMPs and NLRP3 inflammasome engagement in the context of mitochondrial dysfunction, providing mechanistic overlap with the BLUE and PURPLE streams of the SAMHD1 interferonopathy model, and discusses mitochondrial-targeted therapeutics relevant to the treatment-target pathway.
DOI: 10.3390/biom16010120

BTNL2 Inhibits Pyroptosis in H37Ra-Infected Macrophages by Maintaining Mitochondrial Homeostasis (from Microbiology/Infectious Disease)
Yazhi Feng; Yiyao Liu; Guangxin Chen; Changxin Wu — Microorganisms 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA

This paper directly demonstrates the mechanistic convergence of mitochondrial damage → cytosolic mtDNA release → cGAS-STING hyperactivation → NLRP3 transcriptional upregulation → pyroptosis loop that is central to the BLUE and PURPLE streams of the SAMHD1 A565T disease mechanism, albeit in a BTNL2/mycobacterial infection context rather than SAMHD1 haploinsufficiency.
DOI: 10.3390/microorganisms14061188

Senegenin Attenuates LPS-Induced Neuroinflammation and Microglial Cell Death via Akt Phosphorylation and Suppression of cGAS-STING-NLRP3 Signaling: Network Pharmacology and Experimental Validation. (from Ethnopharmacology/Neuropharmacology)
Chandan Chauhan; R. Kaundal — Journal of ethnopharmacology 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, JAK-STAT, treatment-target, POLG-mtDNA, ME-CFS

This paper directly validates suppression of the cGAS-STING-TBK1-IRF3-IFN-β axis alongside NLRP3 inflammasome inhibition and mitochondrial protection (preserved Δψm, reduced mtDNA damage) by a single compound, making senegenin a potentially relevant therapeutic candidate for the convergent interferon-mitochondrial syndrome driven by SAMHD1 haploinsufficiency, though the context is LPS-driven neuroinflammation rather than SAMHD1 or dNTP-pool pathology.
DOI: 10.1016/j.jep.2026.121396

Atrazine increases hepatic inflammation and injury via endoplasmic reticulum (ER) stress mediated excessive formation of mitochondria-associated membranes (MAMs) and activation of the cGAS-STING pathway. (from Environmental toxicology/hepatology)
Zi-Jun Sun; Guanqi Shan; Hui Wan; Yu-xin Zhang; Zhi-Cheng Gao — Environmental pollution 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, clinical-phenotype, other

This paper directly demonstrates the mechanistic cascade of cytosolic mtDNA release → cGAS-STING activation → NLRP3 inflammasome assembly in a hepatic context, precisely mirroring the BLUE and PURPLE loops of the SAMHD1 haploinsufficiency mechanism, and additionally implicates mitochondria-associated membranes (MAMs) and mtROS as intermediaries, offering novel therapeutic targets (4-PBA, MitoQ) relevant to the convergent interferon-mitochondrial syndrome, while also connecting to the family phenotype of hepatic steatosis and inflammation.
DOI: 10.1016/j.envpol.2026.127959

The Autophagy–Inflammation Axis in Kawasaki Disease: Pathogenic Mechanisms and Translational Opportunities (from Pediatric cardiology/vasculitis)
Qiang Xu; Yali Wu; Yan Ding — Journal of Clinical Medicine 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy, mTOR-lysosomal, POLG-mtDNA, treatment-target

This review directly describes the convergent mechanistic triad central to SAMHD1 haploinsufficiency pathology—defective mitophagy and lysosomal dysfunction causing mtDNA release that activates both NLRP3 inflammasome and cGAS-STING pathways driving vascular inflammation—and identifies rapamycin/metformin/resveratrol/urolithin A as therapeutic targets for this axis, providing translational relevance even though SAMHD1 is not mentioned.
DOI: 10.3390/jcm15103918

Understanding Dysfunctional Autophagy and Mitophagy in Inflammatory Cardiovascular Disease (from Cardiology)
Michael E. Kaiser; Toni-ann Lewis; M. Malekan; Manish A. Parikh; Gioia Turitto — Cardiology in Review 2026
Score: 7/10 | Pathways: NLRP3, VDAC1, ISG15-mitophagy, cGAS-STING, POLG-mtDNA, treatment-target, clinical-phenotype

This review directly covers the mechanistic triad central to the disease model—dysfunctional mitophagy (ISG15/MFN1/MFN2/PINK1-Parkin block), NLRP3 inflammasome hyperactivation (including pyroptosis and IL-1β/IL-18 cascades), and mtDNA leakage driving innate immune activation—within the cardiovascular disease context that is a relevant family phenotype, providing treatment-target framing for the RED and PURPLE pathway loops.
DOI: 10.1097/crd.0000000000001302

Pathophysiological mechanisms of post-exertional malaise: an integrative analysis based on the metabolism-immune-neuro interaction model (from Exercise physiology / rehabilitation medicine)
Hongjiao Jin; Yi An; Jingwei Huang; Tingting Luo; Xi Wu — Frontiers in Immunology 2026
Score: 7/10 | Pathways: NLRP3, POLG-mtDNA, ME-CFS, cGAS-STING, ISG15-mitophagy, other

This review directly addresses PEM pathophysiology in ME/CFS and Long COVID through the lens of mitochondrial dysfunction, mtDNA-DAMP activation of NLRP3, ROS overproduction, and disrupted metabolic-immune crosstalk—all core mechanistic streams of the SAMHD1 A565T interferonopathy model, making it highly relevant to the proband's post-viral ME/CFS phenotype even without direct SAMHD1 mention.
DOI: 10.3389/fimmu.2026.1774310

Conjugated bile acids facilitate cholangiocyte senescence to promote cholestatic liver diseases via STING signaling. (from Hepatology)
Guifang Fan; Xin Li; Yiran Li; Shuni Duan; Wenqing Qin — Journal of advanced research 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, clinical-phenotype, treatment-target

This paper directly demonstrates the mechanistic chain of mitochondrial permeability transition pore opening → oxidized mtDNA leakage → STING activation → SASP/inflammasome/pyroptosis in a hepatic cholestatic context, which precisely mirrors the BLUE and PURPLE pathway streams in the SAMHD1 disease model, and the cholecystectomy clustering family phenotype makes hepatobiliary STING activation a clinically actionable bridge.
DOI: 10.1016/j.jare.2026.03.020

Structural and Functional Alterations of MAMs and Their Immunomodulatory Roles in Sepsis‐Induced Lung Injury (from Critical care / pulmonology)
Yihao Wang; Jingran Yang; Xia Li — Journal of Immunology Research 2026
Score: 7/10 | Pathways: VDAC1, NLRP3, POLG-mtDNA, cGAS-STING, ISG15-mitophagy, treatment-target

This review directly addresses VDAC1 (a core player in the BLUE stream mtDNA escape pathway), MFN2 (targeted by ISGylation in the RED stream mitophagy block), NLRP3 inflammasome activation via mitochondrial dysfunction, and mtDNA release as inflammatory triggers—all mechanistically central to SAMHD1 haploinsufficiency pathophysiology, with therapeutic strategies (MFN2 upregulation, MAM integrity restoration) offering translatable treatment targets.
DOI: 10.1155/jimr/9888339

Abstract 6602: Venetoclax enhances radiation-induced anticancer immunity in breast cancer. (from Oncology/Radiation Biology)
E. Guilbaud; Ai Sato; Lorenzo Galluzzi — Cancer Research 2026
Score: 7/10 | Pathways: cGAS-STING, ISG15-mitophagy, VDAC1, JAK-STAT, BIK-cancer, treatment-target

This paper directly characterizes the BAX/BAK→MOMP→cytosolic mtDNA→cGAS/STING→type I IFN axis and its antagonism by mitophagy (ATG5/ATG7-dependent), which is mechanistically identical to the BLUE and RED loops of the SAMHD1 A565T disease model, and Venetoclax (BCL2 inhibitor via BH3-only pathway) represents a pharmacological handle on the same MOMP/mtDNA-release/IFN amplification circuit relevant to the family's interferonopathy and cancer susceptibility phenotypes.
DOI: 10.1158/1538-7445.am2026-6602

🟡 Medium Relevance (Score 5–6)

Review and add to Zotero manually if warranted

Natural Product Treatment for Metabolic Dysfunction-Associated Steatotic Liver Disease: Targeted Mitochondrial Quality Control. (from Hepatology)
Liu Jing; Li Fuxing; Zeng Qianru; Hu Wenxiao; Yang Le — 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy, IRF7-metabolic, POLG-mtDNA, mTOR-lysosomal, treatment-target, clinical-phenotype

This review directly addresses hepatic steatosis (a family phenotype), mtDNA release activating cGAS-STING and TLR9, PINK1/Parkin-mediated mitophagy impairment, and PGC-1α biogenesis—all core pathways in the SAMHD1 haploinsufficiency mechanism—with pharmacological targeting implications, but does not address SAMHD1 or interferonopathy-driven liver disease specifically.
DOI: 10.2147/dddt.s610273

Toxoplasma gondii effector MAF1 blocks mouse AIM2 inflammasome activation by inhibiting mtDNA release. (from Infectious disease / parasitology)
Xiaoyu Zhao; Nadia Holness; Samantha L. Lempke; Lena Pernas; L. Newman — Journal of immunology 2026
Score: 6/10 | Pathways: NLRP3, POLG-mtDNA, cGAS-STING, other

This paper directly demonstrates that cytosolic mtDNA release activates the AIM2 and NLRP3 inflammasomes downstream of IFN-γ priming, mechanistically paralleling the PURPLE and BLUE streams in the SAMHD1 disease model where ox-mtDNA escape through VDAC1 macropores drives inflammasome activation, though the pathogen-specific MAF1/mitochondrial recruitment context is not directly relevant to SAMHD1 haploinsufficiency.
DOI: 10.1093/jimmun/vkaf360

Ag2Se quantum dots neurotoxicity: mitochondrial stress drives ferroptosis-dependent microglial inflammation (from Nanotoxicology/neurotoxicology)
Yongshuai Yao; Zhihui Wang; Chunhui Zhang; Xiaoquan Huang; T. Wei — Journal of Nanobiotechnology 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, mTOR-lysosomal

This paper directly demonstrates the mechanistic chain of mtROS → mtDNA cytoplasmic leakage via mPTP (analogous to VDAC1 macropore) → STING activation → NLRP3 inflammasome in microglia, which closely mirrors the BLUE and PURPLE streams of the SAMHD1 A565T pathomechanism, though the trigger (Ag2Se QDs) is exogenous toxicity rather than dNTP pool expansion.
DOI: 10.1186/s12951-026-04322-4

Role of mitochondrial translation in modulating inflammatory disease outcome: Current knowledge and future perspectives (from Mitochondrial biology / biochemistry)
Swarnali Basu; Rukshar Khan; Shiva Sharma; P. Prajapati; Veena Ammanathan — The Journal of Biological Chemistry 2026
Score: 6/10 | Pathways: NLRP3, POLG-mtDNA, cGAS-STING, mTOR-lysosomal, ME-CFS, treatment-target, other

This review directly addresses mitochondrial translation dysfunction as a driver of NLRP3 inflammasome activation, mtDNA/RNA release as DAMPs, mito-nuclear communication, and mTOR-regulated stress responses—all mechanistically downstream of the POLG-stalling and oxidized mtDNA accumulation predicted in the PURPLE and BLUE streams of the SAMHD1 haploinsufficiency model—but does not address SAMHD1, cGAS-STING, VDAC1, or ISG15 directly.
DOI: 10.1016/j.jbc.2026.111455

Targeting the NLRP3 Inflammasome in Atherosclerosis: A Review of Natural Products and Their Molecular Mechanisms (from Cardiology/Vascular Biology)
Su-Jin Bae; Hye-Min Seo; Si-Eon You; Junho H. Lee — International Journal of Molecular Sciences 2026
Score: 5/10 | Pathways: NLRP3, urate-NLRP3, mTOR-lysosomal, treatment-target, other

This review covers NLRP3 inflammasome biology (a core pathway in the GOLD and PURPLE streams of the disease mechanism) and details natural product inhibitors targeting NLRP3 priming, mitochondrial ROS, and autophagic flux restoration via AMPK/mTOR — all relevant to the convergent interferon-mitochondrial syndrome — but the context is atherosclerosis/ASCVD rather than interferonopathy or SAMHD1, and no direct mechanistic link to cGAS-STING, VDAC1, ISG15, or dNTPase is made.
DOI: 10.3390/ijms27083650

Recalibrating cell fate: targeting the mitochondrial signaling hub with natural active compounds to inhibit regulated cell death in diabetic kidney disease (from Nephrology/diabetic kidney disease)
Yinzhong Dai; Chenguang Wu; Jiaying Zheng; Keqin Zhao; Shimei Hua — Frontiers in Physiology 2026
Score: 5/10 | Pathways: NLRP3, VDAC1, POLG-mtDNA, mTOR-lysosomal, treatment-target, other

This paper covers NLRP3 inflammasome activation by cytosolic mtDNA leakage (via mitochondrial outer membrane permeabilization/VDAC), mitochondrial quality control failure, and regulated cell death crosstalk that are mechanistically parallel to the SAMHD1 haploinsufficiency disease model, but in a diabetic kidney context with no direct connection to SAMHD1, interferonopathy, or the specific molecular players of the family syndrome.
DOI: 10.3389/fphys.2026.1774714

OxLDL-induced ferroptosis and pyroptosis in atherosclerosis: a mini review (from Cardiology/Vascular Biology)
Shaozhi Liu; Yuxia Wu; Lei Chen; Liqin Hu; Jinjin Yin — Frontiers in Immunology 2026
Score: 5/10 | Pathways: NLRP3, VDAC1, urate-NLRP3, other

The paper's focus on NLRP3 inflammasome activation, GSDMD-mediated mitochondrial membrane targeting promoting lipid peroxidation, and bidirectional ferroptosis-pyroptosis crosstalk is tangentially relevant via the NLRP3/mitochondrial damage axis central to the SAMHD1 disease mechanism, but the oxLDL/atherosclerosis context and ferroptosis emphasis are not directly connected to SAMHD1 haploinsufficiency pathways.
DOI: 10.3389/fimmu.2026.1831457

Raccoon dog parvovirus NS1 protein antagonizes type I interferon signaling by promoting selective autophagic degradation of IRF3. (from Veterinary microbiology / virology)
Wenyu Cao; Rui-qi Wang; Jin-Yang Zheng; Ping Ma; Bo Hu — Veterinary microbiology 2026
Score: 5/10 | Pathways: cGAS-STING, ISG15-mitophagy, ME-CFS, other

This paper describes viral antagonism of the cGAS-STING-IRF3 axis via selective autophagic degradation of IRF3, directly implicating the same IRF3/IFN-β/ISG15 nodes central to the SAMHD1 interferonopathy mechanism, and the autophagic targeting of IRF3 offers an oblique parallel to the BECN1-ISGylation mitophagy block in the RED stream, but the context is a veterinary parvovirus with no direct relevance to SAMHD1 haploinsufficiency or human disease.
DOI: 10.1016/j.vetmic.2026.110934

PS4-05-23: Investigating Interferon Pathway Biomarkers as Predictors of Disease Free Survival in Triple Negative Breast Cancer (from Oncology (breast cancer / surgical pathology))
K. Yuan; S. Humble; A. Mabry; R. Kladney; L. Maggi — Clinical Cancer Research 2026
Score: 5/10 | Pathways: ISG15-mitophagy, JAK-STAT, BIK-cancer, other

ISG15 is a core effector in the RED pathway (ISGylation of MFN1/MFN2 and BECN1 causing mitophagy block), and this study directly investigates ISG15 expression as a prognostic biomarker in TNBC alongside ADAR1, providing clinical oncology context for ISG15's role in IFN-driven tumor-immune microenvironment modulation, though SAMHD1 and the specific haploinsufficiency mechanism are not addressed.
DOI: 10.1158/1557-3265.sabcs25-ps4-05-23

🟢 Low Relevance (Score 3–4)

Potential specialty bridges — skim titles

Recent progress in cGAS-STING agonist design and mechanisms of cancer immune modulation. (from oncology/medicinal chemistry)
Wang Liao; Nafees Muhammad; Fei He; Hanif Muhammad; Yang Piaoping — 2026
Score: 4/10 | Pathways: cGAS-STING, treatment-target

This review covers cGAS-STING agonist design for cancer immunotherapy, touching the BLUE pathway's core signaling axis (cGAS→cGAMP→STING→IRF3→IFN-I), but focuses on activating rather than inhibiting this pathway and is oriented toward oncology rather than interferonopathy suppression, making it tangentially relevant at best—the therapeutic direction is opposite to what would benefit SAMHD1 haploinsufficiency patients.
DOI: 10.1039/d6cb00005c

Hyperglycaemia-induced metabolic stress and epigenetic imprinting in the inflammatory pathogenesis of diabetic neuropathy. (from Endocrinology/Neurology)
Faaz Bin Razi; Hamid Ashraf; S. Singhal; Ziaul Qamar; S. Moin — Diabetes research and clinical practice 2026
Score: 4/10 | Pathways: NLRP3, JAK-STAT, POLG-mtDNA, other

The paper discusses NLRP3 inflammasome activation, JAK/STAT signaling, and mitochondrial DNA as DAMPs in a hyperglycemia context, which are mechanistically relevant pathways in the SAMHD1 disease model, but the diabetic neuropathy framing and epigenetic focus are tangential to the core interferonopathy-mitochondrial syndrome without direct mechanistic overlap.
DOI: 10.1016/j.diabres.2026.113172

Antiaging Properties of the Klotho Protein (from Gerontology/nephrology)
G. J. Prud’homme; Qinghua Wang — Cells 2026
Score: 4/10 | Pathways: NLRP3, mTOR-lysosomal, other

Klotho's inhibition of NLRP3 inflammasome and NF-κB, mitochondrial ROS reduction, and autophagy modulation are tangentially relevant to the SAMHD1 interferonopathy-mitochondrial syndrome, but the paper does not address cGAS-STING, ISG15, VDAC1, or the dNTP pool mechanisms central to this disease, making the connection indirect background context only.
DOI: 10.3390/cells15060507

Mechanistic insights into atorvastatin-induced hepatotoxicity: molecular pathways, clinical relevance, and strategies for safer personalized therapy (from hepatology/pharmacology)
Mohammed A Abdel-Rasol; Wael M. El-Sayed — Clinical and Experimental Medicine 2026
Score: 4/10 | Pathways: NLRP3, VDAC1, mTOR-lysosomal, clinical-phenotype, other

The paper touches on NLRP3 inflammasome activation, mitochondrial dysfunction, and bile acid dysregulation in a hepatic context that is tangentially relevant to the family's hepatology phenotype (cholecystectomy clustering, hepatic steatosis) and the NLRP3/mitochondrial damage streams in the disease mechanism, but the focus is on drug-induced hepatotoxicity from atorvastatin rather than any intrinsic innate immune or SAMHD1-related pathway.
DOI: 10.1007/s10238-026-02091-w

Neutrophil extracellular traps in atherothrombosis (from Cardiology/vascular biology)
Ming Xue; Xin Li; Songhai Li; Jing Yang — Chinese Bulletin of Life Sciences 2026
Score: 4/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, urate-NLRP3, other

The paper touches several core pathways (NLRP3 inflammasome, cGAS-STING via mtDNA release, mitochondrial dysfunction) as drivers of NETosis in atherosclerosis, which are mechanistically relevant to the SAMHD1 interferonopathy framework, but the primary subject is NETs in cardiovascular disease and there is no direct connection to SAMHD1, haploinsufficiency, or the specific family phenotype.
DOI: 10.3724/cbls.2026010

Regulated cell death: a multidimensional regulatory network in the pathogenesis of renal fibrosis. (from Nephrology)
Li Wen; Zhou Liang; Zhang Jinji; Sun Jingying; Feng Qing — 2026
Score: 3/10 | Pathways: NLRP3, mTOR-lysosomal, other

This review covers pyroptosis/NLRP3 and autophagy in renal fibrosis context, which are mechanistically relevant pathways in the disease model, but the organ focus (kidney fibrosis) and disease context (renal pathology) are not part of the family phenotype profile, making the connection largely tangential.
DOI: 10.1007/s10495-026-02358-3

ASS1 Promotes Atherosclerotic Inflammation Through the NLRP3/IL-33/ST2 Axis in Ox-LDL–Induced Foam Cells (from Cardiology/Vascular Biology)
Shaoyu Wu; Feihuang Han; Z. Qiao; S. Yuan; Xiaohui Bian — Frontiers in Bioscience-Landmark 2026
Score: 3/10 | Pathways: NLRP3, other

The paper examines NLRP3 inflammasome activation in foam cells via ASS1/STAT3/IL-33, which shares the NLRP3 node with the SAMHD1 disease mechanism, but the upstream driver (ox-LDL/argininosuccinate metabolism in atherosclerosis) is entirely distinct from the dGTP/urate/mtDNA-driven NLRP3 activation in SAMHD1 haploinsufficiency, with no mechanistic overlap in cGAS-STING, VDAC1, ISG15, or mitochondrial dNTP pathways.
DOI: 10.31083/fbl47686

Oxidative Stress and Inflammatory Pathways in Male Infertility: Molecular Mechanisms and Therapeutic Strategies (from andrology/reproductive medicine)
R. Zhankina; N. Tanideh; A. Botabayeva; U. Zhanbyrbekuly — West Kazakhstan Biomedicine Journal 2026
Score: 3/10 | Pathways: NLRP3, other

The paper discusses NLRP3 inflammasome activation and mitochondrial ROS in a reproductive context, which shares surface mechanistic overlap with the NLRP3 and mitochondrial dysfunction arms of the SAMHD1 pathomechanism, but the connection is entirely tangential — it does not address SAMHD1, cGAS-STING, interferonopathy, dNTP pool dysregulation, or any of the core molecular players, and male infertility is not a documented family phenotype.
DOI: 10.4103/wkbj.wkbj_17_26

Precision Neurodegeneration: Integrating Molecular Mechanisms, Biomarkers, and Targeted Therapeutics. (from Neurology/neurodegeneration)
Guizhen Lyu; Dongbing Li — CNS & neurological disorders drug targets 2026
Score: 3/10 | Pathways: NLRP3, ISG15-mitophagy, mTOR-lysosomal

While the paper mentions NLRP3 inflammasome and PINK1-Parkin mitophagy as therapeutic nodes in neurodegeneration, these are discussed in the generic context of Alzheimer's/Parkinson's disease without any mechanistic connection to SAMHD1, interferonopathy, cGAS-STING, or the dNTP pool dysregulation central to the disease profile.
DOI: 10.2174/0118715273435428251202075956

The IFIT3 Protein of Porcine Induces Interferon Signaling and Inhibits the Early Gene Expression of African Swine Fever Virus (from veterinary virology)
Wen-Li Wang; Deng-Wu Han; Xing Yang; Xijuan Shi; Yesheng Shen — Viruses 2026
Score: 3/10 | Pathways: JAK-STAT, ISG15-mitophagy, other

This paper characterizes porcine IFIT3 (ISG60) as an antiviral ISG acting through STAT1/TBK1/IRF3 and JAK-STAT signaling, touching on ISG15 and IRF3 which are nodes in the disease mechanism, but the work is focused on ASFV restriction in swine macrophages with no direct relevance to SAMHD1, human interferonopathy, mitochondrial dysfunction, or the family's clinical phenotypes.
DOI: 10.3390/v18050566

Abstract C043: Novel insights into the immunoregulatory role of radiation activated club cells in non-small cell lung cancer (from Radiation oncology / lung cancer immunology)
Aakanksha R Kapoor; Arshdeep Singh; Bharati Swami; Yongfeng He; Vivek Mittal — Cancer Immunology Research 2026
Score: 3/10 | Pathways: JAK-STAT, ISG15-mitophagy, other

While the paper documents radiation-induced Type I interferon/ISG15/STAT1 upregulation in lung club cells — pathways central to the SAMHD1 interferonopathy mechanism — the context is entirely radiation-oncology/NSCLC tumor microenvironment with no connection to SAMHD1, dNTPase biology, mitochondrial dysfunction, or the family's clinical phenotype.
DOI: 10.1158/2326-6074.io2026-c043

Pathway Coverage This Week

NLRP3: 32 papers
cGAS-STING: 30 papers
POLG-mtDNA: 29 papers
VDAC1: 23 papers
treatment-target: 23 papers
other: 23 papers
ISG15-mitophagy: 16 papers
mTOR-lysosomal: 12 papers
JAK-STAT: 9 papers
ME-CFS: 7 papers
clinical-phenotype: 5 papers
urate-NLRP3: 4 papers
BIK-cancer: 3 papers
dNTPase: 1 papers
AGS-spectrum: 1 papers
IRF7-metabolic: 1 papers

May 24, 2026
in Weekly Digest, cGAS-STING, POLG-mtDNA, VDAC1, treatment-target
3 min read

SAMHD1 Research Digest — 2026-05-24

Generated by samhd1_monitor | Model: claude-sonnet-4-6

Summary: 6 papers evaluated | 4 high-relevance (≥7) | 2 medium (5–6) | 0 low (3–4) | 0 scored <3

🔴 High Relevance (Score 7–10)

Added to Zotero automatically

Mitochondrial DNA-mediated cGAS-STING activation and its crosstalk with NLRP3 inflammasome in chronic obstructive pulmonary disease. (from Pulmonology/Respiratory Medicine)
Jindal Disha; Chopra Vishal; Garg Kranti; Sharma Siddharth — 2026
Score: 8/10 | Pathways: cGAS-STING, NLRP3, POLG-mtDNA, VDAC1, ME-CFS

This paper directly addresses the two core parallel inflammatory streams of the disease model—mtDNA-mediated cGAS-STING activation (BLUE pathway) and NLRP3 inflammasome crosstalk (PURPLE/GOLD pathways)—in a context of chronic oxidative mtDNA damage and cytosolic mtDNA release, mechanistically mirroring the SAMHD1 haploinsufficiency syndrome even though COPD is the disease context.
DOI: 10.1016/j.cytogfr.2026.05.001

Piezo1 mediates hypoxia-induced endometriosis fibrosis via the mtDNA -dependent cGAS-STING pathway. (from Gynecology/reproductive medicine)
Ouyang Zhuqing; Zhang Lanyue; Tan Jiarong; Shen Fujin — 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, clinical-phenotype

This paper directly demonstrates the mtDNA leakage → cGAS-STING activation axis as a driver of fibrosis, a core Blue pathway mechanism in the SAMHD1 syndrome, and contextualizes it in a gynecological tissue relevant to the family's endometrial carcinoma phenotype, while the Ca²⁺-dependent mitochondrial damage mechanism provides a novel upstream trigger converging on the same cGAS-STING node.
DOI: 10.1186/s12967-026-08255-2

Mitochondrial DNA release contributes to neuropathic pain via a cGAS-STING-IRF3-CMPK2-associated immunometabolic feedback mechanism. (from Neurology/pain medicine)
Wang Bo; Zeng Hui; Zhan Hongrui; Xu Yin; Hu Ziwei — 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, VDAC1, ME-CFS, other

This paper directly characterizes an IRF3-CMPK2 positive feedback loop downstream of mtDNA-cGAS-STING activation — where CMPK2 (a dNTP synthesis enzyme) sustains mitochondrial stress and mtDNA release — which maps precisely onto the BLUE stream (VDAC1→mtDNA escape→cGAS→STING→IRF3) of the SAMHD1 haploinsufficiency mechanism, and introduces CMPK2-mediated dNTP pool dysregulation as a novel amplification node that is highly relevant to the dNTPase-deficient context of SAMHD1 p.A565T; NDGA as a pharmacological inhibitor of this loop also represents a potential treatment target.
DOI: 10.1186/s12967-026-08314-8

Jintiange ameliorates age-related sarcopenia by inhibiting the cGAS-STING signaling pathway via maintaining mitochondrial homeostasis. (from Ethnopharmacology/Musculoskeletal medicine)
Xu Yuan; Li Xiao-Li; Guo Yi-Xun; Wu Ruo-Bing; He Ming-Chao — 2026
Score: 7/10 | Pathways: cGAS-STING, ISG15-mitophagy, POLG-mtDNA, treatment-target, other

This paper directly demonstrates that inhibiting cGAS-STING via mitochondrial homeostasis maintenance (PGC-1α biogenesis, MFN1 dynamics, PINK1/Parkin mitophagy) ameliorates sarcopenia, hitting three of the four core disease streams (BLUE cGAS-STING, RED ISGylation-mitophagy block, PURPLE mtDNA quality) simultaneously, and identifies a treatment modality acting upstream of the same nodes relevant to SAMHD1 haploinsufficiency pathology.
DOI: 10.1016/j.jep.2026.121873

🟡 Medium Relevance (Score 5–6)

Review and add to Zotero manually if warranted

A novel bifunctional peptide predicted to target neuropeptide Y4 and GLP-1 receptors alleviates cognitive deficits in 5 × FAD mice by modulating cGAS-STING-mediated neuroinflammation. (from Neurology/Alzheimer's disease pharmacology)
Feng Yijie; Zhang Caili; Wei Yinuo; Liu Enhua; Sun Hongyu — 2026
Score: 6/10 | Pathways: cGAS-STING, POLG-mtDNA, NLRP3, treatment-target, other

This paper directly demonstrates that cytosolic mtDNA release activates cGAS-STING-IRF3-IL-1β neuroinflammatory signaling (a core Loop A/B pathway in the SAMHD1 disease model) and that pharmacological suppression of this axis is therapeutically beneficial, providing mechanistic and treatment-relevant data for the mtDNA-cGAS-STING cascade central to SAMHD1 haploinsufficiency, albeit in an AD rather than interferonopathy context.
DOI: 10.1016/j.bcp.2026.118074

Fucoxanthin improves stomatitis by regulating mitochondrial function and cGAS-STING signaling. (from Dentistry/oral medicine)
Lin Caipeng; Deng Lili; Xie Xi; Luo Hai-Bin; Liu Deyu — 2026
Score: 5/10 | Pathways: cGAS-STING, POLG-mtDNA, treatment-target, other

This paper demonstrates that mitochondrial dysfunction leads to mtDNA release activating cGAS-STING (directly relevant to the BLUE stream of the disease mechanism), and identifies fucoxanthin as a direct cGAS/STING inhibitor with molecular docking evidence, but the context is stomatitis/oral mucositis rather than any of the core family phenotypes, making it an indirect therapeutic lead rather than mechanistically central.
DOI: 10.1038/s41598-026-53680-4

Pathway Coverage This Week

cGAS-STING: 6 papers
POLG-mtDNA: 6 papers
other: 4 papers
VDAC1: 3 papers
treatment-target: 3 papers
NLRP3: 2 papers
ME-CFS: 2 papers
clinical-phenotype: 1 papers
ISG15-mitophagy: 1 papers

May 17, 2026
in Weekly Digest, cGAS-STING, VDAC1, POLG-mtDNA, treatment-target
6 min read

SAMHD1 Research Digest — 2026-05-17

Generated by samhd1_monitor | Model: claude-sonnet-4-6

Summary: 12 papers evaluated | 7 high-relevance (≥7) | 3 medium (5–6) | 2 low (3–4) | 0 scored <3

🔴 High Relevance (Score 7–10)

Added to Zotero automatically

NOX2 inhibitor baicalein alleviates rheumatoid arthritis and inactivating mitochondrial oxidative stress-mediated cGAS-STING signaling in fibroblast-like synoviocytes. (from Rheumatology)
Wang Rui; Fang Weiming; Qiao Yansheng; Zhang Xin; Gao Yuan — 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, treatment-target, clinical-phenotype, other

This paper directly characterizes the NOX2→mtROS→VDAC1 oligomerization→mtDNA release→cGAS-STING axis in rheumatoid arthritis fibroblast-like synoviocytes, precisely mapping the BLUE-stream mechanism (VDAC1 macropore → cytosolic mtDNA → cGAS → STING → IFN-I) that is central to the SAMHD1 A565T interferonopathy model, while also identifying baicalein as a pharmacological intervention point and linking it to a clinically relevant autoimmune phenotype present in the family.
DOI: 10.1016/j.phymed.2026.158268

Macrophage TRPML1 ameliorates post-myocardial infarction inflammation by blocking VDAC1 oligomerization to prevent ferroptosis and cGAS-STING activation. (from Cardiology (post-myocardial infarction inflammation and cardiac repair))
Zhao Xiuye; Wang Jia; Wang Zhenru; Du Haonan; Li Hongda — 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, NLRP3, POLG-mtDNA, treatment-target, mTOR-lysosomal

This paper directly demonstrates that VDAC1 oligomerization drives mtDNA cytosolic escape → cGAS-STING activation → pro-inflammatory cytokine storm in macrophages, and identifies VDAC1 inhibition (NSC 15364) as a therapeutic rescue strategy — mechanistically identical to the BLUE stream of the SAMHD1 A565T syndrome (SAMHD1/VDAC1 interaction loss → VDAC1 macropore → cytosolic mtDNA → cGAS → STING → IFN-I), making it highly relevant as both mechanistic validation and a potential treatment target.
DOI: 10.1016/j.freeradbiomed.2026.05.006

Tempol alleviates autoimmune uveitis by targeting the oxidative stress-mediated cGAS-STING-NF-kB signaling pathway to restore M1/M2 macrophage polarization balance. (from Ophthalmology/Autoimmune uveitis)
Xu Shuqin; Feng Jiaye; Peng Yuan; Xu Furu; Liu Yunfeng — 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, ISG15-mitophagy, treatment-target, other

This paper directly demonstrates the oxidative stress → mitochondrial damage → cytosolic mtDNA release → cGAS-STING-NF-κB → IFN-β → M1 macrophage polarization axis with impaired PINK1/Parkin mitophagy, which maps precisely onto the BLUE and RED streams of the SAMHD1 haploinsufficiency mechanism, and identifies Tempol (a superoxide dismutase mimetic/ROS scavenger) and STING inhibitor H-151 as therapeutic interventions that restore mitophagy flux and suppress interferon output—directly actionable for the family's convergent interferon-mitochondrial syndrome.
DOI: 10.1016/j.intimp.2026.116798

Mitochondrial dysfunction due to myeloid TFAM loss limits senolytic efficacy in allergic airway inflammation. (from Pulmonology/Allergy)
Nguyen Jackie; Van Courtney; Olverson Zianne A; Sampath Neil; Posham Lalithya — 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, VDAC1, ISG15-mitophagy, other

This paper directly demonstrates that TFAM loss causes cytosolic mtDNA accumulation activating cGAS-STING signaling in macrophages, driving senescence-associated inflammation — a mechanistic parallel to the SAMHD1 BLUE pathway where VDAC1 macropore release of mtDNA fragments activates cGAS-STING-IRF3-IFN-I, and the finding that mitochondrial DNA maintenance failure amplifies innate immune activation is directly relevant to understanding how SAMHD1 haploinsufficiency sustains chronic interferonopathy via cytosolic mtDNA.
DOI: 10.1093/ajrcmb/aanag101

MSTO1 modulates RAD51 activity to safeguard mitochondrial DNA integrity and control immune responses. (from mitochondrial biology / rare neuromuscular disease)
Cheng Kaiqi; Xu Zhanzhan; Liu Jiansong; Pan Yichen; Nie Chen — 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, VDAC1, ME-CFS, other

MSTO1 deficiency causes RAD51-mediated mtDNA damage, BAX/BAK-dependent mtDNA leakage activating cGAS-STING inflammation—directly paralleling the BLUE stream (VDAC1 macropore → cytosolic mtDNA → cGAS → IFN-I) and POLG-mtDNA integrity mechanisms central to the SAMHD1 A565T interferonopathy model, offering a novel upstream regulator of the same mtDNA-immune axis.
DOI: 10.1038/s41417-026-01032-9

α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication. (from Neuroscience/neurodegeneration)
Chakraborty Ranabir; Maya Stephanie; Testa Veronica; Montero-Muñoz Jara; Nonaka * — 2026
Score: 7/10* | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, mTOR-lysosomal, other

This paper directly demonstrates the mechanistic chain of mitochondrial damage → cytosolic mtDNA release → cGAS-STING-IRF3 activation that constitutes Loop A/B of the SAMHD1 haploinsufficiency model, and further shows that damaged mitochondria are transferred intercellularly and degraded via lysosomal pathways, with NF-κB and IRF3 driving inflammatory amplification—all core molecular players in the disease mechanism, albeit in a synucleinopathy context rather than SAMHD1-specific.
DOI: 10.1038/s41467-026-73136-7

Mechano-metabolic feedback connects tissue fluidity to mitochondrial DNA-dependent immunity in breast cancer. (from Oncology / tumor mechanobiology)
Palamidessi Andrea; Frittoli Emanuela; Corada Monica; Martini Emanuele; Barzaghi — 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, BIK-cancer, other

This paper directly demonstrates a mtDNA-release → cGAS-STING → innate immune hyperinflammation axis in cancer, mediated by BAX/BAK outer mitochondrial membrane permeabilization and GASDERMIN A oligomerization, which is mechanistically analogous to the SAMHD1/VDAC1 macropore → cytosolic mtDNA → cGAS-STING loop (Loop A/B) in the disease model, and provides novel upstream (mechano-metabolic, mitochondrial fission via AMPK-AKAP1-DRP1) and downstream (tumor immunogenicity, checkpoint sensitivity) context relevant to SAMHD1 haploinsufficiency-driven interferonopathy and cancer susceptibility.
DOI: 10.1038/s41467-026-71795-0

🟡 Medium Relevance (Score 5–6)

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cGAS-STING Signalling in the tumour microenvironment: Implications for immune surveillance and therapeutic strategies. (from Oncology / tumour immunology)
Al-Adayleh Teeb Yasir Mahmoud; Ahmad Waqas; Rahiman Siti Sarah Fazalul; Murugaiy — 2026
Score: 6/10 | Pathways: cGAS-STING, JAK-STAT, POLG-mtDNA, mTOR-lysosomal, treatment-target, other

This review covers the cGAS-STING pathway in depth—including mtDNA release as a trigger, STING-NF-κB crosstalk, autophagy interactions, and pharmacological modulators—all directly relevant to the BLUE stream of the SAMHD1 interferonopathy mechanism, but is framed entirely around oncology/TME rather than monogenic interferonopathy or SAMHD1 haploinsufficiency.
DOI: 10.1016/j.intimp.2026.116832

O-GlcNAcylation of p66Shc drives senescence associated secretory phenotype via mitochondrial DNA release in gestational diabetes mellitus†. (from Obstetrics/reproductive medicine)
Zhu Hengxuan; Ji Lulu; Lai Rujie; Nai Yaru; Yang Xiting — 2026
Score: 6/10 | Pathways: cGAS-STING, POLG-mtDNA, pregnancy-fetal, other

This paper directly demonstrates cytoplasmic mtDNA release activating cGAS/STING to drive senescence-associated secretory phenotype and inflammation in a gestational/placental context, which is mechanistically adjacent to the BLUE stream (VDAC1→mtDNA→cGAS→STING→IFN-I) and relevant to the pregnancy-fetal phenotype dimension of the family profile, though the driver is p66Shc O-GlcNAcylation under high glucose rather than SAMHD1 haploinsufficiency.
DOI: 10.1093/biolre/ioag090

Recent advances in dual-function fluorescent ligands targeting mitochondrial DNA G-Quadruplexes for Cancer Theranostics. (from oncology/chemical biology)
Hu Ming-Hao — 2026
Score: 6/10 | Pathways: cGAS-STING, POLG-mtDNA, NLRP3, VDAC1, treatment-target, other

This review is adjacently relevant because mtG4-targeting ligands directly perturb mitochondrial DNA integrity and dNTP pool dynamics (core to SAMHD1 haploinsufficiency pathology), activate cGAS-STING via cytosolic mtDNA release, and trigger NLRP3-associated PANoptosis—all three major mechanistic streams (BLUE, PURPLE, GOLD) of the SAMHD1 interferonopathy model—while the cancer theranostics framing connects to the family's oncological phenotypes (prostate, myeloma, endometrial cancers) and offers potential treatment-target insights via mitochondrial metabolic collapse strategies.
DOI: 10.1016/j.bmc.2026.118697

🟢 Low Relevance (Score 3–4)

Potential specialty bridges — skim titles

A prognostic model based on nucleotide metabolism genes in osteosarcoma. (from oncology)
Ju Songli; Tao Lu; Li Xuyan; Huang Nijiao; Ke Xixian — 2026
Score: 4/10 | Pathways: dNTPase, BIK-cancer, IRF7-metabolic, other

SAMHD1 is included as one of seven nucleotide metabolism genes in an osteosarcoma prognostic model, confirming its role in metabolic reprogramming and tumor suppression, but the paper does not investigate SAMHD1 mechanism, haploinsufficiency, dNTPase activity, or any of the core interferon-mitochondrial pathways relevant to this disease profile.
DOI: 10.1007/s12672-026-05036-7

A cell-impermeable kinase inhibitor uncovers outside-in signaling pathways that promote HIV-1 infection. (from Virology/HIV research)
Vinzant Kelsey; Cheshenko Natalia; Pan Heng; Cutler Ronald; Buckler Joshua N — 2026
Score: 4/10 | Pathways: dNTPase, other

The paper touches on SAMHD1 only as a CDK-phosphorylation target (phospho-SAMHD1 inactivating its dNTPase activity to promote HIV infection), which is tangentially related to the core disease mechanism of reduced SAMHD1 dNTPase activity, but the study is focused on HIV entry/infection mechanisms and exofacial signaling rather than interferonopathy, mitochondrial dysfunction, or any pathway directly relevant to the A565T haploinsufficiency syndrome.
DOI: 10.1128/jvi.00160-26

Pathway Coverage This Week

other: 11 papers
cGAS-STING: 10 papers
VDAC1: 8 papers
POLG-mtDNA: 8 papers
treatment-target: 5 papers
mTOR-lysosomal: 3 papers
NLRP3: 2 papers
ISG15-mitophagy: 2 papers
BIK-cancer: 2 papers
dNTPase: 2 papers
clinical-phenotype: 1 papers
ME-CFS: 1 papers
JAK-STAT: 1 papers
pregnancy-fetal: 1 papers
IRF7-metabolic: 1 papers

May 10, 2026
in Weekly Digest, cGAS-STING, treatment-target, JAK-STAT, POLG-mtDNA
17 min read

SAMHD1 Research Digest — 2026-05-10

Generated by samhd1_monitor | Model: claude-sonnet-4-6

Summary: 37 papers evaluated | 12 high-relevance (≥7) | 20 medium (5–6) | 5 low (3–4) | 0 scored <3

🔴 High Relevance (Score 7–10)

Added to Zotero automatically

Mitochondrial 8-Oxoguanine DNA Glycosylase 1–Mitochondrial Permeability Transition Pore Axis Drives Mitochondrial DNA Escape and Accelerates Osteoarthritis Progression (from Orthopedics/osteoarthritis)
Shiqian Huang; Heting Yu; Weizhong Qi; Na Lin; Jianmao Chen — Research 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, NLRP3, treatment-target, other

This paper directly demonstrates the OGG1-mPTP axis driving oxidized mtDNA escape → cytosolic mtDNA → cGAS-STING-NF-κB activation, mechanistically recapitulating the BLUE and PURPLE streams of the SAMHD1 A565T syndrome (VDAC1/mPTP-mediated mtDNA release and ox-mtDNA from impaired mitochondrial repair both feeding cGAS-STING), while cyclosporin A (mPTP inhibitor) and TH10785 (OGG1 activator) as intervention targets are directly translatable to therapeutic strategies for the dNTP pool expansion–driven mitochondrial pathology in SAMHD1 haploinsufficiency.
DOI: 10.34133/research.1235

Crosstalk between cGAS-STING and pyroptosis: From molecular mechanisms to therapeutic strategies. (from Pharmacology/drug discovery)
Hongquan Wang; Shuang Wu; Xuan Zhang; WeiHua Zheng; Zhiji Wang — International immunopharmacology 2026
Score: 8/10 | Pathways: cGAS-STING, NLRP3, VDAC1, treatment-target, AGS-spectrum, ME-CFS

This review directly addresses the cGAS-STING–pyroptosis (NLRP3/caspase-1) crosstalk that constitutes Loops A and B of the SAMHD1 haploinsufficiency mechanism, covers therapeutic targeting strategies including upstream nucleic acid sensing, core pathway modulation, and downstream effector control that map precisely onto proposed interventions (IMSB301, MCC950, VBIT-4), and frames these in autoimmune/interferonopathy and sterile inflammation contexts highly relevant to the family's convergent interferon-mitochondrial syndrome.
DOI: 10.1016/j.intimp.2026.116203

Emerging molecular mechanisms of cGAS-STING activation and regulation. (from Structural/molecular biology)
Yilin Liu; Kanglong Ma; Zhengfan Jiang — Molecular immunology 2026
Score: 8/10 | Pathways: cGAS-STING, JAK-STAT, AGS-spectrum, ME-CFS, treatment-target

This review directly covers the cGAS-STING pathway (Loop A in the disease mechanism), including structural activation by dsDNA, cGAMP synthesis and STING translocation, and novel regulatory mechanisms (sGAGs, biocondensates, manganese-independent activation) that are directly relevant to understanding how VDAC1 macropore-released cytosolic mtDNA fragments drive IRF3→IFN-I signaling in SAMHD1 haploinsufficiency, and identifies therapeutic targets applicable to this interferonopathy.
DOI: 10.1016/j.molimm.2026.02.008

The cGAS-STING pathway and mitochondrial metabolism: from mechanistic insights to therapeutic potential in tumor (from oncology)
Kui Zhao; Siyuan Cui; Na Wang; Qi Wei; Xuerui Wang — Journal of Translational Medicine 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, JAK-STAT, mTOR-lysosomal, treatment-target, IRF7-metabolic

This review directly addresses the cGAS-STING/mitochondrial metabolism axis—the BLUE stream of the disease mechanism—including mtDNA escape, STING spatiotemporal dynamics, and metabolic crosstalk that mirrors the interferonopathy-mitochondrial loop in SAMHD1 haploinsufficiency, while the treatment-target discussion of STING agonist optimization and metabolic modulation has translational relevance for the family's interferonopathy management.
DOI: 10.1186/s12967-026-07748-4

Mitochondrial DNA 6mA Methylation by METTL4 Drives Neuroinflammation via cGAS-STING Activation in Vascular Cognitive Impairment. (from Neurology/cerebrovascular)
Z. Gong; Ziyi Chen; Shuixian Sang; Lingfei Yang; H. Qin — Free radical biology & medicine 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, VDAC1, other

This paper directly demonstrates the mechanistic axis of oxidized mtDNA leakage activating cGAS-STING neuroinflammation—a core BLUE stream pathway in the SAMHD1 haploinsufficiency model—and introduces METTL4-mediated mtDNA epigenetic modification as an upstream driver of mtDNA escape, impaired ETC activity, and ROS production that converges on the same cGAS-STING-mediated inflammatory cascade relevant to the proband's interferon-mitochondrial syndrome.
DOI: 10.1016/j.freeradbiomed.2026.01.019

The roles of the mtDNA-cGAS-STING axis in tumor immunity: from immune activation to immune evasion (from Oncology/tumor immunology)
Na Huang; Zheng Liu; Haibo Lei; Xiang Liu — Frontiers in Immunology 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, JAK-STAT, IRF7-metabolic, BIK-cancer, treatment-target

This review directly covers the mtDNA-cGAS-STING-IRF3-IFN-I axis (the BLUE stream of the disease mechanism) in comprehensive detail, including mtDNA leakage triggers, cGAMP synthesis, downstream IFN-I induction, and therapeutic targeting strategies (STING modulators, nano-delivery), all of which are core to SAMHD1 haploinsufficiency pathophysiology, though the tumor immunity framing is tangential to the primary interferonopathy/ME-CFS phenotype.
DOI: 10.3389/fimmu.2025.1739559

mtDNA leakage promotes neuron-glia crosstalk to induce epilepsy by cGAS-STING-driven neuroinflammation and serine metabolic reprogramming. (from Neurology/Epileptology)
Jie Jiang; Meiling Zuo; Kehan Zhao; Zhihao Ling; Zhida Wu — Proceedings of the National Academy of Sciences of the United States of America 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, NLRP3, treatment-target, other

This paper directly demonstrates the mtDNA leakage → cGAS-STING → neuroinflammation axis in a CNS context, with pharmacologic STING inhibition (H-151) suppressing disease, providing mechanistic and therapeutic validation for the BLUE stream of the SAMHD1 haploinsufficiency model, while also introducing a novel metabolic reprogramming downstream consequence (D-serine/NMDA excitotoxicity) that could explain neurological phenotypes (ASD/ADHD, possible seizure susceptibility) in the family.
DOI: 10.1073/pnas.2522313123

Protective and pathogenic: The Janus-faced role of cGAS-STING in the brain. (from Neurology/cerebrovascular)
C. Corona; Christina Kanzlemar; A. Hussaini; R. Ratan — Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 2026
Score: 7/10 | Pathways: cGAS-STING, JAK-STAT, IRF7-metabolic, ME-CFS, AGS-spectrum, mTOR-lysosomal

This paper directly characterizes cGAS-STING/IFN-I signaling as enforcing a 'metabolic austerity program' that suppresses synaptic plasticity when chronically activated—a mechanism highly relevant to the SAMHD1 A565T family's neurocognitive phenotypes (AuDHD, cognitive fatigue, ME/CFS) driven by constitutive BLUE-stream cGAS-STING activation, and the distinction between transient vs. sustained IFN-I activation maps directly onto the haploinsufficiency's tonic low-grade interferonopathy.
DOI: 10.1177/0271678X261427904

CircZBTB44-Encoded Peptide ZBTB44-342aa Alleviates Aortic Valve Calcification Via cGAS-STING Inhibition. (from Cardiology / valvular disease)
Dongtu Hu; Yingwen Lin; Hai-Bo Huang; G. Xian; Yubing Chen — Circulation research 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, treatment-target

This paper directly demonstrates that mtDNA cytosolic release activates cGAS-STING to drive pathological osteogenic differentiation, and identifies STING inhibition (H-151) as therapeutic—mechanistically parallel to the BLUE stream (VDAC1 → mtDNA escape → cGAS → STING → IRF3 → IFN-I) central to the SAMHD1 A565T syndrome, with the added novel mechanistic detail that IGF2BP3 suppresses mitochondrial damage and mtDNA release upstream of cGAS-STING.
DOI: 10.1161/CIRCRESAHA.125.326771

Targeting the cGAS-STING-TBK1 pathway in cancer therapy. (from Oncology)
Leyao Jiang; Y. Zhong; Zilong Zhang; Qicheng Yang; Shengting Sun — Future medicinal chemistry 2026
Score: 7/10 | Pathways: cGAS-STING, JAK-STAT, IRF7-metabolic, treatment-target, BIK-cancer

This review directly covers the cGAS-STING-TBK1 axis—the BLUE stream core pathway in the disease mechanism—including its dual role in cancer (relevant to SAMHD1 tumor suppressor function) and targeted therapeutic agents such as STING agonists/antagonists and TBK1 inhibitors that represent treatment candidates for the interferonopathy component of the syndrome.
DOI: 10.1080/17568919.2026.2628553

Abstract 389: GSDMB drives cGAS-STING-mediated immune evasion in HER2-amplified colorectal cancer. (from Oncology (colorectal cancer / HER2-amplified CRC))
Junyong Weng; Tianchen Xiong; Xinxiang Li; Ajay Goel — Cancer Research 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, JAK-STAT, BIK-cancer, other

GSDMB-driven mitochondrial membrane pore formation causing chronic low-level mtDNA leakage into the cytosol activating cGAS-STING with downstream IFNα response directly mirrors the BLUE pathway (VDAC1 macropore → cytosolic mtDNA → cGAS → STING → IRF3 → IFN-I) central to SAMHD1 haploinsufficiency, and demonstrates a novel pore-forming mechanism linking mitochondrial integrity loss to chronic interferonopathy in a cancer context relevant to the family's BIK-cancer axis.
DOI: 10.1158/1538-7445.am2026-389

Integrative transcriptomic profiling links telomere dysfunction to cGAS–STING activation in heart failure signatures in mice and humans (from Cardiology)
M. Brandt; S. Khraisat; Q. Luo; M. Mayerle; U. Raaz — Cardiovascular Research 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, JAK-STAT, ISG15-mitophagy, clinical-phenotype

This paper provides first direct evidence that telomere shortening activates cGAS-STING → type I interferon signaling in cardiomyocytes via a telomere-p53-mitochondria axis, directly paralleling the BLUE and RED streams of the SAMHD1 haploinsufficiency mechanism (cytosolic DNA → cGAS → STING → IRF3 → IFN-I → JAK-STAT), and contextualizes interferon-driven cardiac dysfunction as a clinically relevant endpoint relevant to the family's interferonopathy cardiovascular risk.
DOI: 10.1093/cvr/cvag013

🟡 Medium Relevance (Score 5–6)

Review and add to Zotero manually if warranted

Simultaneous activation of apoptosis and cGAS-STING pathway with a mitochondria-targeted dehydrocholic acid compound for enhanced hepatocellular carcinoma chemoimmunotherapy. (from Oncology/pharmacology)
Fuwei Li; Sizhe Zhu; Xinyu Sun; Guangxing Geng; Jiawen Zhao — Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2026
Score: 6/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, BIK-cancer, treatment-target

This paper directly demonstrates the mechanistic link between mitochondrial permeability transition pore opening, cytosolic mtDNA release, and cGAS-STING activation in hepatocellular carcinoma — recapitulating the BLUE stream of the SAMHD1 haploinsufficiency mechanism (VDAC1 macropore → cytosolic mtDNA → cGAS → STING → IRF3 → IFN-I) and is further relevant given the family's hepatic phenotype (hepatic steatosis, cholecystectomy clustering) and SAMHD1's tumor suppressor role, though the context is therapeutic oncology rather than constitutive interferonopathy.
DOI: 10.1016/j.biopha.2026.119044

Spleen Tyrosine Kinase (SYK) is Necessary for cGAS‐STING Signaling in Müller Glia and Visual Function Deficits in Diabetic Mice (from Ophthalmology/Retinal Neuroscience)
Esma I. Yerlikaya; S. Sunilkumar; Sandeep M. Subrahmanian; Allyson L. Toro; Clay — Glia 2026
Score: 6/10 | Pathways: cGAS-STING, VDAC1, NLRP3, JAK-STAT, other

This paper directly demonstrates the mechanistic link between mitochondrial membrane permeability → cytosolic mtDNA → cGAS-STING → NF-κB → IL-1β/CCL2 (MCP-1) activation, which maps precisely onto the BLUE stream of the SAMHD1 haploinsufficiency model, and introduces SYK as a novel required intermediary in cGAS-STING signaling with potential therapeutic targeting relevance, though the disease context is diabetic retinopathy rather than SAMHD1 dysfunction.
DOI: 10.1002/glia.70155

Pharmacological activation of cGAS-STING pathway to reverse cancer drug resistance. (from oncology)
Yumin Wang; Yan Wang; Q. Gao; Yonglin Zhu; Yulin Li — Pharmacology & therapeutics 2026
Score: 6/10 | Pathways: cGAS-STING, JAK-STAT, treatment-target, BIK-cancer, other

This review directly covers the cGAS-STING pathway—a core Loop A mechanism in SAMHD1 haploinsufficiency—and describes how epigenetic, post-translational, and metabolic suppression of cGAS-STING promotes drug resistance, which is directly relevant to understanding modulators of this pathway and potential therapeutic targets, though the oncology framing (reactivating a suppressed pathway) is the mirror-image of the disease context here (a constitutively hyperactive cGAS-STING from SAMHD1 loss-of-function), making it an adjacent rather than direct mechanistic match.
DOI: 10.1016/j.pharmthera.2026.108991

Mangiferin inhibits cGAS-STING pathway-related inflammation via Nrf2 activation to protect against sepsis-induced heart injury (from Cardiology/Traditional Chinese Medicine)
Junna Song; Meng Wang; Qian Li; Wanting Zhao; Xiangming Chen — Chinese Medicine 2026
Score: 6/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, treatment-target, other

This paper directly addresses mtDNA release, mitochondrial membrane integrity (mPTP/VDAC-adjacent), and cGAS-STING-driven cardiac inflammation with a natural compound (mangiferin/Nrf2) that suppresses the same cGAS-STING axis central to the SAMHD1 interferonopathy mechanism, offering a potentially translatable treatment angle for the interferon-mitochondrial syndrome, though the context is LPS-sepsis rather than SAMHD1 haploinsufficiency.
DOI: 10.1186/s13020-026-01329-9

Selenium regulates pyroptosis through the ROS-mtDNA-cGAS-STING axis to alleviate trimethyltin chloride-induced inflammation in chicken kidneys. (from Veterinary toxicology / comparative physiology)
Huiling Zheng; Xinyu Huo; Wenwen Zhang; Shuang Lou; Mingyue Li — Comparative biochemistry and physiology. Toxicology & pharmacology : CBP 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, POLG-mtDNA, treatment-target, other

This paper directly demonstrates the ROS→mitochondrial dysfunction→mtDNA leakage→cGAS-STING→NLRP3/pyroptosis cascade (BLUE and PURPLE streams) and validates selenium as a therapeutic modulator of this axis, providing mechanistic and pharmacological context highly relevant to the SAMHD1 interferonopathy model where the same mtDNA-cGAS-STING-NLRP3 convergence is central, though the disease context (organotin nephrotoxicity in chickens) is entirely distinct from SAMHD1 haploinsufficiency.
DOI: 10.1016/j.cbpc.2026.110452

The Role of the cGAS-STING Pathway in Central Nervous System Diseases (from Neurology)
Xiangning He; Xunlu Yin; Qian Chen; Haoyuan Gao; Fangfang Zhao — CNS & Neurological Disorders - Drug Targets 2026
Score: 6/10 | Pathways: cGAS-STING, JAK-STAT, IRF7-metabolic, treatment-target, ME-CFS

This review directly covers the cGAS-STING pathway (BLUE stream) in CNS disease contexts including neuroinflammation, autophagy, and apoptosis, with therapeutic inhibitors discussed (C-176, H-151, RU.521), which are directly relevant to the SAMHD1/VDAC1/cGAS/STING axis driving neurological manifestations (AuDHD, ME/CFS, potential dystonia) in this family, though it lacks SAMHD1-specific or mitochondrial dNTP-pool mechanistic content.
DOI: 10.2174/0118715273428657260309045542

Lipids Meet Immunity: Metabolic Control of cGAS-STING (from Lipidology/Immunometabolism)
C. Mah; Xuan Yuan Aw; Ngee Kiat Chua — Lipidology 2026
Score: 6/10 | Pathways: cGAS-STING, IRF7-metabolic, mTOR-lysosomal, other

This review directly addresses metabolic regulation of the cGAS-STING pathway—the BLUE stream core mechanism—through lipid biology, covering how lipid metabolism (including membrane compartmentalization, cholesterol, fatty acids) modulates STING activation and signaling dynamics, which is directly relevant to the VDAC1-mtDNA-cGAS-STING axis in this disease and adjacent to the hepatic steatosis and metabolic reprogramming phenotypes observed in the family.
DOI: 10.3390/lipidology3010010

The roles of cGAS-STING pathway in cancer (from Oncology)
Jijun Sun; Ruijuan Wang; Jue Wang; Lele Zhang — Oncology and Translational Medicine 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, IRF7-metabolic, BIK-cancer, treatment-target, clinical-phenotype

This review directly covers the cGAS-STING pathway (BLUE stream core mechanism) with extensions into pyroptosis/NLRP3 crosstalk and cancer contexts relevant to the family's tumor phenotypes (multiple myeloma, endometrial, prostate, duodenal cancers), and discusses STING agonists/inhibitors as therapeutic targets, but does not address SAMHD1, mitochondrial mechanisms, ISG15-mitophagy, or VDAC1 specifically.
DOI: 10.1097/ot9.0000000000000136

Resveratrol Mitigates Age-Associated Cognitive Decline via Inhibition of cGAS-STING-Mediated Microglial Senescence (from Neuroscience/gerontology)
Xinxin Duan; Jiahui Cheng; Jiayao Wang; Wen Chen; Zhi Ruan — Cells 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, JAK-STAT, ME-CFS, treatment-target

This paper directly investigates cGAS-STING pathway suppression as a therapeutic target for neuroinflammation and cognitive decline, with downstream IL-1β and CXCL-10 reduction highly relevant to the BLUE and RED streams of the SAMHD1 interferonopathy mechanism, and resveratrol's mechanism (potentially via SIRT1/PGC-1α activation and cGAS inhibition) offers a plausible treatment-target insight for managing chronic IFN-I signaling in SAMHD1 haploinsufficiency, though the context is aging/galactose-induced senescence rather than SAMHD1 mutation.
DOI: 10.3390/cells15060523

TRIM69 potentiates the cGAS-STING signalling pathway by promoting STING ubiquitination. (from Virology/antiviral innate immunity)
Shixin Chen; Li Yi; Mengzhou Xue; Chunfu Zheng — Cellular signalling 2026
Score: 6/10 | Pathways: cGAS-STING, JAK-STAT, treatment-target

TRIM69-mediated K63-ubiquitination of STING enhances cGAS-STING-IFN-I signaling, directly relevant to the BLUE stream where SAMHD1/VDAC1 loss drives cytosolic mtDNA→cGAS→STING→IRF3→IFN-I, as a novel positive regulator that could amplify the already dysregulated interferonopathy in this family; however, no direct SAMHD1, mitochondrial, or clinical phenotype connection is demonstrated.
DOI: 10.1016/j.cellsig.2026.112495

cGAS-STING signaling: a therapeutic target in inflammatory bowel disease and related colorectal cancer (from Gastroenterology/Oncology)
Xi Chen; Xiaohua Tang; Sixuan Chen; Yang Ye; Fei Mao — Frontiers in Immunology 2026
Score: 6/10 | Pathways: cGAS-STING, JAK-STAT, NLRP3, treatment-target, IRF7-metabolic, clinical-phenotype

This review directly covers the cGAS-STING pathway (a core BLUE stream component in the disease mechanism) and its bidirectional regulation including IFN-I and proinflammatory cytokine production, with therapeutic targeting implications relevant to interferonopathy management, though it focuses on intestinal disease contexts rather than SAMHD1 haploinsufficiency or mitochondrial pathology specifically.
DOI: 10.3389/fimmu.2025.1709908

Targeting the cGAS-STING pathway in ophthalmology: from innate immunity to therapeutic innovation. (from Ophthalmology)
Dan Yan; Weijie Ouyang; Kuanshu Li; Xuguang Sun — Experimental eye research 2026
Score: 6/10 | Pathways: cGAS-STING, JAK-STAT, mTOR-lysosomal, AGS-spectrum, treatment-target, clinical-phenotype

This review directly covers the cGAS-STING pathway (BLUE stream core mechanism) with therapeutic targeting implications, and notably flags glaucoma as a cGAS-STING-driven ocular disease—glaucoma appears in the tracked family phenotype list—providing a mechanistic bridge between the interferonopathy and a documented familial clinical feature, while the autophagy/senescence/cell-death interactions also touch ISG15-mitophagy and mTOR-lysosomal axes.
DOI: 10.1016/j.exer.2026.110978

Cell-type specific activation of the cGAS-STING pathway in tumor immunotherapy: mechanisms and therapeutic implications (from Oncology/Cancer Immunotherapy)
Lusheng Wang; Sudi Zhu; Zhixian Ding; Jie Hong; Lijie Zheng — Journal of Translational Medicine 2026
Score: 5/10 | Pathways: cGAS-STING, JAK-STAT, IRF7-metabolic, treatment-target

This paper covers cGAS-STING signaling comprehensively in the tumor immunotherapy context, including cell-type-specific activation dynamics, chronic vs. acute signaling consequences, and therapeutic modulation strategies that are mechanistically relevant to the SAMHD1 haploinsufficiency disease model (where dysregulated cGAS-STING via VDAC1 macropore/mtDNA escape drives Loop A), but the focus is entirely oncologic/immunotherapeutic rather than interferonopathy or SAMHD1-related disease.
DOI: 10.1186/s12967-025-07645-2

Cutaneous human papillomavirus E6 impairs the cGAS-STING pathway (from Virology/Dermatology-oncology)
Grant Brooke; D. Dacus; Rose Pollina; Katsura Asano; N. Wallace — mSphere 2026
Score: 5/10 | Pathways: cGAS-STING, JAK-STAT, other

This paper directly characterizes cGAS-STING pathway suppression by a viral protein (β-HPV E6), which is mechanistically relevant to the BLUE stream of the disease model where cytosolic dsDNA activates cGAS→STING→IRF3→IFN-I, but the context is viral immune evasion in skin cancer rather than SAMHD1 haploinsufficiency, making it an indirect connection that illuminates cGAS-STING modulation without direct mechanistic import to the family phenotype.
DOI: 10.1128/msphere.00859-25

Calibrating the RT-cGAS-STING axis to drive cold-to-hot tumor transformation: mechanistic foundations and translational strategies for combination with immunotherapy (from Radiation oncology / tumor immunology)
Yi-fan Kang; Jin-ming Chen; Bai Xu; Jun-Nv Xu; Qixian Qin — Molecular Cancer 2026
Score: 5/10 | Pathways: cGAS-STING, IRF7-metabolic, JAK-STAT, treatment-target, other

This review covers the cGAS-STING-IFN-I axis in depth (Loop A of the disease mechanism) and discusses regulatory nodes like TREX1 and apoptotic caspases, with translational treatment implications, but is framed entirely within radiotherapy-oncology and does not address SAMHD1, mitochondrial dNTP pools, VDAC1, ISG15-mitophagy, or the interferonopathy-fatigue spectrum relevant to this family.
DOI: 10.1186/s12943-026-02636-3

cGAS-STING Signaling Pathway in Urogenital Oncology: Regulation, Resistance, and Routes to Response. (from Oncology/Urology)
Chen Gong; Senmao Li; Ying Huang; Enxiu Luo; Zhiyong Tan — Critical reviews in oncology/hematology 2026
Score: 5/10 | Pathways: cGAS-STING, JAK-STAT, IRF7-metabolic, BIK-cancer, treatment-target

This review covers cGAS-STING signaling in urogenital oncology with mechanistic detail on phosphorylation/ubiquitination regulation, STING agonists, and interferon competence circuits that are directly relevant to the BLUE stream of the SAMHD1 mechanism, and touches on prostate cancer (BIK-axis family phenotype), but remains oncology-focused and does not address SAMHD1, mitochondrial dysfunction, ISG15-mitophagy, or the interferonopathy/ME-CFS clinical context.
DOI: 10.1016/j.critrevonc.2026.105222

Loss of XRCC1 promotes cGAS/STING mediated innate immune signaling in gastric cancer (from Oncology/gastroenterology)
Aashirwad Shahi; Shengyuan Zhao; Julia A. Goewey Ruiz; Dawit Kidane — Molecular Medicine 2026
Score: 5/10 | Pathways: cGAS-STING, other

This paper mechanistically demonstrates that nuclear DNA repair deficiency (XRCC1 loss) triggers cytosolic DNA accumulation and cGAS/STING-mediated type I interferon signaling, which is directly analogous to the BLUE stream in the SAMHD1 A565T model where dNTP pool imbalance and VDAC1 dysfunction release mtDNA to activate cGAS/STING, but the specific molecular actors (XRCC1 vs. SAMHD1, nuclear SSBs vs. cytosolic dNTP/mtDNA) and clinical context (gastric cancer vs. interferonopathy) are sufficiently distinct to limit direct translational relevance.
DOI: 10.1186/s10020-026-01429-0

Abstract A003: Chronic cGAS–STING activation reprograms glioblastoma-associated macrophages toward immunosuppression in hypoxic tumor niches (from Neuro-oncology)
Sebastian Ouyang; Virginia Wertman; Michael Brown; Matthew S. Waitkus; Justin T. — Cancer Research 2026
Score: 5/10 | Pathways: cGAS-STING, JAK-STAT, IRF7-metabolic, other

This paper directly investigates cGAS-STING signaling and demonstrates that chronic/sustained STING activation leads to loss of interferon signaling and metabolic reprogramming, which is mechanistically relevant to understanding how the constitutive low-level cGAS-STING activation hypothesized in SAMHD1 haploinsufficiency might paradoxically shift toward immunosuppression over time, but the context is glioblastoma tumor immunology rather than interferonopathy or mitochondrial disease.
DOI: 10.1158/1538-7445.brain26-a003

Venezuelan Equine Encephalitis Virus Antagonizes the cGAS-STING Pathway (from Virology/Infectious Disease)
Brittany N. Heath; Maryna Akhrymuk; Abdullahi Temitope Jamiu; I. Akhrymuk; A. Pi — Cells 2026
Score: 5/10 | Pathways: cGAS-STING, ISG15-mitophagy, JAK-STAT, ME-CFS, other

This paper directly investigates cGAS-STING pathway modulation by an RNA virus (VEEV), demonstrating viral antagonism of STING phosphorylation and noncanonical ISG induction, which is mechanistically relevant to the BLUE and RED streams of the SAMHD1 syndrome (where dysregulated cGAS-STING drives IFN-I → ISGylation → mitophagy block), and the post-viral ME/CFS trigger context (adenovirus/SARS-CoV-2 in proband), but the connection is indirect as VEEV is not a documented trigger and no SAMHD1 or haploinsufficiency data are presented.
DOI: 10.3390/cells15040327

Pueraria flavones attenuate DSS-induced colitis by regulating the microbiota-bile acid-FXR/TGR5 axis and suppressing mtDNA-cGAS-STING signaling (from Gastroenterology/Pharmacognosy)
Liheng Kang; Chunsheng Feng; Ziyi Tang; Wanping Gu; Ying Wang — iScience 2026
Score: 5/10 | Pathways: cGAS-STING, POLG-mtDNA, other

This paper directly demonstrates the mtDNA-release → cGAS-STING axis as a colitis driver and its suppression by a therapeutic agent, which is mechanistically relevant to the BLUE stream (VDAC1/mtDNA/cGAS/STING/IFN-I) of the SAMHD1 syndrome, but the colitis context, plant flavone intervention, microbiota-bile acid framing, and absence of any interferonopathy/SAMHD1 connection make it only an indirect mechanistic parallel rather than a directly actionable finding.
DOI: 10.1016/j.isci.2026.115275

🟢 Low Relevance (Score 3–4)

Potential specialty bridges — skim titles

C5aR1 and cGAS/STING and their possible involvement in radiosensitivity of colorectal cancer (from Oncology/Radiation Oncology)
Trang Thao Quoc Pham; Pei-Ju Lee; Nguyen Quoc Khanh Le — iScience 2026
Score: 4/10 | Pathways: cGAS-STING, other

The paper discusses cGAS/STING in the context of colorectal cancer radiosensitivity and complement C5a/C5aR1 suppression of STING-driven IFN-beta, which touches the cGAS-STING pathway central to the BLUE stream, but the oncologic and radiotherapy framing is tangential to the SAMHD1 haploinsufficiency interferonopathy mechanism and adds no direct mechanistic or clinical insight relevant to the family phenotype.
DOI: 10.1016/j.isci.2026.115009

Targeting redox metabolism and low-dose radiotherapy synergistically activate cGAS-STING pathway to improve NK cell therapy efficacy in hepatocellular carcinoma (from Oncology/Nanomedicine)
Bo Liu; Wenjia Kong; Xijie Zhang; Bo Ren; Yusheng Cheng — Journal of Nanobiotechnology 2026
Score: 4/10 | Pathways: cGAS-STING, treatment-target, other

This paper involves cGAS-STING pathway activation as a mechanism but in the context of HCC tumor immunotherapy via redox manipulation and NK cell recruitment, with no connection to SAMHD1 haploinsufficiency, interferonopathy, mitochondrial dNTP pools, or any family phenotype; the cGAS-STING relevance is mechanistically superficial relative to the disease profile.
DOI: 10.1186/s12951-026-04171-1

EEPD1 Inhibition Unleashes Antitumor Immunity in Colorectal Cancer by Activating the cGAS‐STING Pathway (from oncology)
L. Huo; Chong Wu; Xiaobo Li; Caina Ma; Jiaming Huang — Advanced Science 2026
Score: 4/10 | Pathways: cGAS-STING, other

This paper activates cGAS-STING via cytosolic DNA from genomic instability (HR deficiency), which shares the cGAS-STING-type I interferon axis central to the SAMHD1 mechanism, but the driver is nuclear DNA damage rather than dNTP pool dysregulation or mtDNA escape, and the clinical context (CRC immunotherapy sensitization) is only tangentially related to the SAMHD1 interferonopathy syndrome.
DOI: 10.1002/advs.202522826

Biomimetic Iridium‐Based Photothermal Nanozyme to Trigger Ferroptosis and Pyroptosis and Activate the cGAS‐STING Pathway for Improved Tumor Immunotherapy (from Oncology/Nanomedicine)
Lijun Ding; Zhongxiong Fan; Guoyu Xia; Fukai Zhu; N. Yang — Advanced Science 2026
Score: 4/10 | Pathways: cGAS-STING, NLRP3, POLG-mtDNA, other

This oncology nanomedicine paper deliberately induces mtDNA oxidative damage and cGAS-STING activation as a therapeutic mechanism for tumor immunotherapy, touching on core pathways (cGAS-STING, pyroptosis/NLRP3, mtDNA release) relevant to the SAMHD1 disease model, but entirely in an artificial photothermal/ROS cancer context with no connection to SAMHD1 haploinsufficiency, interferonopathy, or the family phenotype.
DOI: 10.1002/advs.202519186

Leveraging Naturally Assembled Tumor Extracellular Vesicles as Self-Adjuvanting Nanovaccines to Potentiate Cancer Immunotherapy via cGAS/STING Activation. (from Oncology/nanomedicine)
Jianing Gong; K. Liang; Yinzhe Sun; Laozhi Xie; Yukun Huang — ACS nano 2026
Score: 3/10 | Pathways: cGAS-STING, other

This paper exploits cGAS/STING activation as a cancer immunotherapy tool using engineered extracellular vesicles, which is mechanistically adjacent to the BLUE stream of the disease profile but is focused on therapeutic oncology engineering rather than providing any mechanistic insight into SAMHD1 haploinsufficiency, interferonopathy, or the pathological consequences of dysregulated cGAS-STING signaling relevant to the family phenotype.
DOI: 10.1021/acsnano.5c15637

Pathway Coverage This Week

cGAS-STING: 37 papers
treatment-target: 22 papers
other: 20 papers
JAK-STAT: 20 papers
POLG-mtDNA: 12 papers
IRF7-metabolic: 12 papers
VDAC1: 11 papers
NLRP3: 9 papers
BIK-cancer: 7 papers
ME-CFS: 6 papers
AGS-spectrum: 4 papers
mTOR-lysosomal: 4 papers
clinical-phenotype: 4 papers
ISG15-mitophagy: 2 papers

May 3, 2026
in Weekly Digest, POLG-mtDNA, cGAS-STING, treatment-target, VDAC1
3 min read

SAMHD1 Research Digest — 2026-05-03

Generated by samhd1_monitor | Model: claude-sonnet-4-6

Summary: 5 papers evaluated | 3 high-relevance (≥7) | 1 medium (5–6) | 1 low (3–4) | 0 scored <3

🔴 High Relevance (Score 7–10)

Added to Zotero automatically

Nucleotide metabolism reprogramming in obesity-associated cardiovascular inflammation: a new perspective (from Cardiology/Immunometabolism)
Taoming Qian; Mei Zhang; Yuhan Liu; Donghao Guo; Juan Jin — Frontiers in Immunology 2026
Score: 9/10 | Pathways: dNTPase, NLRP3, POLG-mtDNA, urate-NLRP3, treatment-target, clinical-phenotype, other

This paper directly models the SAMHD1-inhibition → cytosolic dNTP accumulation → mitochondrial dNTP import (SLC25/PNC transporters) → mtDNA oxidation → NLRP3 hyperactivation axis that is the PURPLE stream of the disease mechanism, proposes therapeutic nodes at SLC25 inhibition and SAMHD1-preserving kinase modulation, and validates the mechanistic framework in a cardiovascular/macrophage context highly relevant to the family's cardiac and inflammatory phenotypes.
DOI: 10.3389/fimmu.2026.1829718

Nickel exposure promotes aortic dissection progression by binding to VDAC1 and activating the cGAS-STING pathway in vascular smooth muscle cells. (from Cardiology/Vascular Surgery)
Xiao Zhihao; Jin Jing; Long Xiangxing; Zhu Xu; Jiao Jian — 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, NLRP3, treatment-target, other

This paper directly demonstrates the VDAC1 oligomerization → mtDNA leakage → cGAS-STING activation axis in a cardiovascular cell type, mechanistically validating the BLUE stream of the SAMHD1 haploinsufficiency model, and identifies VBIT-12 (closely related to VBIT-4, a key treatment target in this disease) as an inhibitor of this pathway, providing direct mechanistic and therapeutic relevance.
DOI: 10.1016/j.jhazmat.2026.142122

SETD2 Deficiency Drives Mitochondrial DNA Leakage and Creates a Druggable Dependency on BCL-XL in Clear Cell Renal Cell Carcinoma. (from Oncology (clear cell renal cell carcinoma / tumor suppressor biology))
Uprety Anusha; Judd Chandler; Villella Emily D; Keller Rebecca; Wagner Ryan — 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, BIK-cancer, POLG-mtDNA, treatment-target

This paper directly demonstrates the mechanistic link between cytoplasmic mtDNA leakage → cGAS-STING activation → IRF3 → apoptotic priming via BH3-only proteins (NOXA/MCL-1/BCL-xL), which parallels the BLUE and RED streams of the SAMHD1 A565T mechanism (VDAC1 macropore → mtDNA escape → cGAS-STING → IRF3), and also engages the BIK-cancer axis relevant to the family's solid tumor phenotypes, while introducing BCL-xL as a druggable synthetic lethal node downstream of chronic innate immune mtDNA sensing.
DOI: 10.1158/0008-5472.can-25-3195

🟡 Medium Relevance (Score 5–6)

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ATP-Responsive Bimetallic Metal-Organic Frameworks Amplify Oxidative Stress in the Tumor Microenvironment for Synergistic Chemo-Immunotherapy. (from Oncology/Nanomedicine)
Li You; Zhang Wenxin; Xu Zitao; Ma Shixin; Xiong Yufei — 2026
Score: 5/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, other

This paper mechanistically demonstrates that Zn2+-induced mitochondrial dysfunction causes mtDNA leakage into the cytosol, activating cGAS-STING signaling—a core pathway in the SAMHD1 haploinsufficiency mechanism (BLUE stream via VDAC1 macropore → cytosolic mtDNA → cGAS → STING → IFN-I), but the context is entirely tumor-focused nanomedicine with no connection to SAMHD1, interferonopathy, or the family phenotype.
DOI: 10.3390/jfb17040199

🟢 Low Relevance (Score 3–4)

Potential specialty bridges — skim titles

GE11/RGD Dual-Ligand Copper Nanoassemblies Synchronize Cuproptosis and Photothermal Therapy for Targeted Cervical Cancer Ablation. (from Oncology/nanomedicine)
Yang Nan; Liu Lu; Ding Lu; Chen Zhen; Su Tianyuan — 2026
Score: 4/10 | Pathways: cGAS-STING, POLG-mtDNA, other

The paper demonstrates that mtDNA leakage from mitochondrial collapse activates the cGAS-STING-IRF3 pathway as an anti-tumor mechanism, which is mechanistically relevant to the BLUE stream of the disease model, but in the context of copper-induced cuproptosis in cervical cancer with no connection to SAMHD1, interferonopathy, or the family phenotype.
DOI: 10.1021/acs.molpharmaceut.6c00002

Pathway Coverage This Week

POLG-mtDNA: 4 papers
other: 4 papers
cGAS-STING: 4 papers
treatment-target: 3 papers
VDAC1: 3 papers
NLRP3: 2 papers
dNTPase: 1 papers
urate-NLRP3: 1 papers
clinical-phenotype: 1 papers
BIK-cancer: 1 papers

April 26, 2026
in Weekly Digest, cGAS-STING, treatment-target, NLRP3, JAK-STAT
5 min read

SAMHD1 Research Digest — 2026-04-26

Generated by samhd1_monitor | Model: claude-sonnet-4-6

Summary: 10 papers evaluated | 4 high-relevance (≥7) | 5 medium (5–6) | 1 low (3–4) | 0 scored <3

🔴 High Relevance (Score 7–10)

Added to Zotero automatically

TH5487 specifically targets NLRP3 in FCAS patients resistant to MCC950. (from Autoinflammatory/rare disease (FCAS - Familial Cold Autoinflammatory Syndrome))
Lackner Angela; Picucci Sofia I; Jiang Wenjin; Onyuru Janset; Campos Melissa — 2026
Score: 8/10 | Pathways: NLRP3, POLG-mtDNA, cGAS-STING, treatment-target, ME-CFS

This paper directly addresses NLRP3 inflammasome inhibition via a novel hOGG1/oxidized-mtDNA sensing mechanism, demonstrates cryo-EM evidence of NLRP3-mitochondrial DNA association, shows TH5487 works where MCC950 fails (critical for treatment-resistant cases), and reveals that NLRP3 inhibition simultaneously increases type I interferon responses—all highly relevant to the PURPLE and BLUE pathways of the SAMHD1 haploinsufficiency mechanism where ox-mtDNA drives NLRP3 activation (Loop B) and cGAS-STING drives IFN-I (Loop A).
DOI: 10.1038/s42003-026-10008-2

Sesamin ameliorates high-fat diet-induced inflammation and metabolic dysfunction in pregnant uterine smooth muscle via cGAS-STING inhibition. (from Obstetrics/maternal-fetal medicine)
Xu Chenyi; Li Xuan; Yang Chen; Xing Ting; Yang Longtao — 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, POLG-mtDNA, pregnancy-fetal, treatment-target, IRF7-metabolic

This paper directly demonstrates the mtDNA leakage → cGAS-STING → IL-1β/IL-18 axis in a metabolic-inflammatory context with mitochondrial dysfunction, and identifies sesamin as a STING inhibitor that blocks this pathway — mechanistically overlapping with the BLUE and PURPLE streams of the SAMHD1 syndrome, while the pregnancy/uterine context is relevant to the obstetric phenotype dimension of the family.
DOI: 10.1016/j.phymed.2026.158182

TREM2 & senescent macrophages fuel inflammaging and metabolic dysfunction-associated steatotic liver disease. (from Hepatology/Geroscience)
Salladay-Perez Ivan A; Avila Itzetl; Estrada Lizeth; Alexandru Andreea C; Ponce * — 2026
Score: 7/10* | Pathways: cGAS-STING, NLRP3, VDAC1, JAK-STAT, IRF7-metabolic, POLG-mtDNA, mTOR-lysosomal, clinical-phenotype, treatment-target

This paper directly demonstrates that cytosolic mitochondrial DNA drives type I interferon signaling in senescent macrophages causing MASLD and inflammaging—mechanistically overlapping with the BLUE (cGAS-STING via mtDNA escape) and GOLD (liver/metabolic) streams of the SAMHD1 A565T syndrome, and the hepatic steatosis and cholecystectomy clustering phenotypes tracked in the family, with senolytic treatment as a novel therapeutic angle.
DOI: 10.1038/s43587-026-01101-6

Efficacy of JAK1/2 inhibitors in AGS genes-related interferonopathies: A multicenter retrospective observational study with treated vs untreated comparison. (from Pediatric neurology / rare disease genetics)
G. Marinella; Ylenia Vaia; Davide Politano; J. Galli; F. Nicita — Molecular genetics and metabolism 2026
Score: 7/10 | Pathways: JAK-STAT, AGS-spectrum, treatment-target, cGAS-STING, ISG15-mitophagy, ME-CFS, clinical-phenotype

This multicenter retrospective study directly evaluates baricitinib and ruxolitinib (JAK1/2 inhibitors) in AGS-related type I interferonopathies—the same therapeutic class most relevant to SAMHD1 haploinsufficiency-driven IFN-I overproduction—and critically notes that pathogenetic complexity extends beyond JAK-STAT, implying residual disease burden from parallel NLRP3/VDAC1/ISG15 streams that mirror the multi-loop mechanism of the documented family syndrome.
DOI: 10.1016/j.ymgme.2026.109907

🟡 Medium Relevance (Score 5–6)

Review and add to Zotero manually if warranted

MRE11A Regulates Sepsis Through the mtDNA/STING Pathway of T Lymphocyte Apoptosis (from Pediatric critical care / sepsis immunology)
Wei Zhixin; Wang Feifei; Qin Pengji; Yang Zhiyong — 2026
Score: 6/10 | Pathways: cGAS-STING, POLG-mtDNA, ME-CFS, other

This paper directly demonstrates the mtDNA-cytosol → cGAS → STING axis driving T lymphocyte apoptosis via MRE11A loss, mechanistically paralleling the BLUE stream in SAMHD1 haploinsufficiency where cytosolic mtDNA fragments activate cGAS-STING-IRF3-IFN-I, with the added implication that MRE11A-mediated mtDNA containment failure (analogous to VDAC1 macropore-driven mtDNA escape) amplifies cGAS-STING signaling and immune exhaustion relevant to post-viral ME/CFS and immunodysfunction phenotypes in the family.
DOI: 10.21203/rs.3.rs-9414184/v1

18-β-glycyrrhetinic acid facilitates nuclear-mitochondrial communications to alleviate oxidative stress through HMGB1-cGAS-Mul1 axis in tendinopathy. (from Orthopaedics/musculoskeletal biology)
Gao Yuan-Yuan; Sun Wen-Shuang; Sun Zi-Ying; Wang Jun-Rui; Lv Zhong-Yang — 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, treatment-target, other

This paper directly characterizes a novel cGAS degradation mechanism via Mul1 ubiquitin ligase and HMGB1 methylation that suppresses cGAS-STING-NLRP3 signaling under oxidative stress—highly relevant as a potential therapeutic axis for the BLUE and PURPLE streams of the SAMHD1 haploinsufficiency syndrome, though the clinical context (tendinopathy) is entirely orthogonal to the family phenotype.
DOI: 10.1186/s12967-026-08091-4

Towards effective targeted therapies in morphea. (from Dermatology)
Amanda M Saracino; L. Iyengar; M. Nikpour — Italian journal of dermatology and venereology 2026
Score: 6/10 | Pathways: JAK-STAT, AGS-spectrum, cGAS-STING, treatment-target, clinical-phenotype

Morphea is characterized here as a type I interferonopathy enriched for IFN-I pathways, directly overlapping the BLUE/RED streams of the SAMHD1 mechanism, and JAK inhibitors (baricitinib, ruxolitinib class) are flagged as emerging treatments—the same class relevant to managing SAMHD1-driven interferonopathy—making this an adjacent clinical phenotype with shared molecular architecture and therapeutic implications.
DOI: 10.23736/S2784-8671.25.08413-0

Targeting cytokine pathways: the role of biologics in autoinflammatory disorders (from Rheumatology/rare disease)
T. Koga — Expert Review of Clinical Immunology 2026
Score: 6/10 | Pathways: NLRP3, JAK-STAT, AGS-spectrum, treatment-target, clinical-phenotype, IRF7-metabolic

This review directly covers interferonopathies and inflammasomopathies including their molecular mechanisms (IL-1/NLRP3, JAK-STAT/type I IFN) and therapeutic targeting with JAK inhibitors and IL-1 biologics, which are directly relevant to the SAMHD1 haploinsufficiency syndrome's dual NLRP3 and type I interferonopathy streams and potential treatment strategies, though SAMHD1 itself is not mentioned.
DOI: 10.1080/1744666X.2026.2625277

Discovering patterns in the pathologic significance of non-missense deleterious variants in RELA. (from Clinical Immunology / Rare Autoinflammatory Disease)
H. Hayakawa; M. Tsumura; Takanori Utsumi; H. Nihira; Wei-Te Lei — The Journal of allergy and clinical immunology 2026
Score: 5/10 | Pathways: JAK-STAT, AGS-spectrum, clinical-phenotype, other

RELA haploinsufficiency vs. dominant-negative distinction with type I interferonopathy overlap is conceptually analogous to SAMHD1 haploinsufficiency mechanisms, and the identification of DN variants driving interferonopathy beyond HI phenotypes parallels the SAMHD1 heterozygous pathogenic framework, but RELA/NF-κB is a parallel inflammatory axis not directly in the SAMHD1 mechanistic streams (cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy).
DOI: 10.1016/j.jaci.2026.01.020

🟢 Low Relevance (Score 3–4)

Potential specialty bridges — skim titles

Systematic discovery of pro- and anti-HIV host factors in primary human CD4+ T cells. (from virology)
Rathore Ujjwal; Dugan Eli; Thornton Hunter; Kumar Vigneshwari Easwar; Dajani Ram — 2026
Score: 3/10 | Pathways: dNTPase, other

This paper studies HIV host factors in CD4+ T cells using CRISPR screens and identifies restriction factors including cyclophilin paralogs and viral entry modulators, tangentially relevant only because SAMHD1 is a known HIV restriction factor (dNTPase/Vpx target) but the paper does not study SAMHD1, its dNTPase activity, or any of the core cGAS-STING/NLRP3/mitochondrial pathways relevant to the A565T haploinsufficiency syndrome.
DOI: 10.1016/j.cell.2026.03.046

Pathway Coverage This Week

cGAS-STING: 7 papers
treatment-target: 7 papers
NLRP3: 5 papers
JAK-STAT: 5 papers
clinical-phenotype: 5 papers
POLG-mtDNA: 4 papers
AGS-spectrum: 4 papers
other: 4 papers
ME-CFS: 3 papers
IRF7-metabolic: 3 papers
pregnancy-fetal: 1 papers
VDAC1: 1 papers
mTOR-lysosomal: 1 papers
ISG15-mitophagy: 1 papers
dNTPase: 1 papers

April 22, 2026
in Weekly Digest, cGAS-STING, POLG-mtDNA, VDAC1, NLRP3
30 min read

SAMHD1 Research Digest — 2026-04-22

Generated by samhd1_monitor | Model: claude-sonnet-4-6

Summary: 18 papers evaluated | 6 high-relevance (≥7) | 7 medium (5–6) | 5 low (3–4) | 0 scored <3

🔴 High Relevance (Score 7–10)

Added to Zotero automatically

Mitochondrial Dysfunction and Immunoinflammatory Remodeling in Heart Failure: Emerging Role of the mtDNA-cGAS/STING Axis and Therapeutic Opportunities. (from Cardiology)
Zhang Xi; Xia Xiangchen; Zhang Yanmin; Liu Xiaomin; Wei Xiaoyu — 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, ISG15-mitophagy, NLRP3, treatment-target, clinical-phenotype

This review directly addresses the mtDNA-cGAS/STING axis as a self-sustaining immunoinflammatory loop driven by mitochondrial quality control failure (impaired mitophagy, oxidative stress, mtDNA leakage as DAMPs), which maps precisely onto the BLUE and RED streams of the SAMHD1 A565T mechanism, and discusses small-molecule cGAS/STING inhibitors and mitophagy enhancers that are directly therapeutically relevant to the disease profile, with the added clinical phenotype bridge of cardiac remodeling/heart failure as a potential manifestation of the interferonopathy-mitochondrial syndrome.
DOI: 10.1016/j.phrs.2026.108195

Mitochondrial 8-Oxoguanine DNA Glycosylase 1-Mitochondrial Permeability Transition Pore Axis Drives Mitochondrial DNA Escape and Accelerates Osteoarthritis Progression. (from Rheumatology/Orthopedics (osteoarthritis))
Huang Shiqian; Yu Heting; Qi Weizhong; Lin Na; Chen Jianmao — 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, treatment-target, other

This paper directly demonstrates the OGG1-mPTP axis driving oxidized mtDNA escape into the cytosol activating cGAS-STING-NF-κB signaling, which maps precisely onto the BLUE stream (VDAC1/mtDNA→cGAS→STING→IRF3→IFN-I) and PURPLE stream (ox-mtDNA production via POLG stalling) of the SAMHD1 haploinsufficiency mechanism, with cyclosporin A (mPTP inhibitor, analogous to VDAC1 targeting) and OGG1 activation as potential therapeutic nodes relevant to mitigating the mtDNA-escape-driven interferonopathy in this family.
DOI: 10.34133/research.1235

Targeting VDAC1 to protect against mitochondria-linked cell death pathways: apoptosis, pyroptosis, ferroptosis, and associated diseases. (from Cell biology/neurology (Alzheimer's disease model))
Shteinfer-Kuzmine A; Nivedita A Karunanithi; Santhanam M; Trishna S; Swerdlow R * — 2026
Score: 8/10* | Pathways: VDAC1, NLRP3, cGAS-STING, ISG15-mitophagy, POLG-mtDNA, treatment-target

This paper directly characterizes VDAC1 oligomerization as a master regulator of apoptosis, pyroptosis, and ferroptosis, validates VBIT-4 and VBIT-12 as multi-pathway inhibitors blocking NLRP3 inflammasome assembly and mitochondrial dysfunction—precisely targeting the BLUE stream (VDAC1 macropore → cytosolic mtDNA → cGAS-STING) and PURPLE stream (mitochondrial dysfunction → NLRP3) that are core to the SAMHD1 A565T haploinsufficiency mechanism, while VBIT-4 is already listed as a key therapeutic candidate for this syndrome.
DOI: 10.1007/s10495-025-02217-7

Micropterus salmoides rhabdovirus G protein interacts with VDAC to trigger mitochondrial DNA/cGAS-STING pathway-mediated antiviral immune responses. (from Aquatic virology/fish immunology)
Zhu Qiang; Gu Xie; Zhao Lu-Chuan; Zhang Ze-Sheng; Huang Meng-Meng — 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, other

This paper directly demonstrates the mechanistic link between VDAC1/2 oligomerization, cytosolic mtDNA release, and cGAS-STING pathway activation—precisely the BLUE stream of the disease mechanism—showing that viral glycoprotein interaction with VDAC triggers mtDNA escape and IFN-I induction, validating the VDAC1→mtDNA→cGAS→STING axis central to SAMHD1 haploinsufficiency pathophysiology, albeit in a teleost fish model.
DOI: 10.1016/j.fsi.2026.111353

Microglial NEDD4L activates mtDNA-cGAS-STING pathway and promotes neuroinflammation after intracerebral hemorrhage through impairing mitophagy (from Neurology/acute brain injury (intracerebral hemorrhage))
Wang Jin; Ma Yuyuan; Yang Kaichuang; Zhang Weihua; Wang Weiyu — 2026
Score: 7/10 | Pathways: cGAS-STING, ISG15-mitophagy, POLG-mtDNA, JAK-STAT

This paper directly demonstrates that NEDD4L-mediated ubiquitination of Parkin impairs mitophagy, causing mtDNA leakage into the cytoplasm and cGAS-STING activation, with STAT2-dependent transcriptional upregulation of NEDD4L — directly paralleling the RED (ISGylation-Parkin block) and BLUE (mtDNA-cGAS-STING) mechanistic streams central to SAMHD1 haploinsufficiency, and identifying Parkin ubiquitination as a novel regulatory node in the mitophagy-block → mtDNA escape → interferonopathy axis.
DOI: 10.21203/rs.3.rs-9225741/v1

ADT-OH promotes mitophagy and suppresses the cytosolic mtDNA-cGAS-STING inflammatory cascade in microglia. (from Neurology/neurodegeneration (Parkinson's disease/microglia))
Hou Xiao-Ou; Wang Miao; Deng Rong; Lu Yi-Fan; Zhang Jin-Ru — 2026
Score: 7/10 | Pathways: cGAS-STING, ISG15-mitophagy, POLG-mtDNA, treatment-target, other

This paper directly demonstrates that restoring mitophagic flux (via PINK1-PARKIN activation) prevents cytosolic mtDNA accumulation and suppresses the cGAS-STING inflammatory cascade — precisely the BLUE and RED pathway loops central to SAMHD1 haploinsufficiency pathology — and identifies ADT-OH (H2S donor) as a potential therapeutic modality, offering a novel mechanistic and treatment-relevant angle for the double mitophagy block caused by ISGylation of MFN1/MFN2 and BECN1.
DOI: 10.1038/s41401-026-01789-7

🟡 Medium Relevance (Score 5–6)

Review and add to Zotero manually if warranted

Spleen Tyrosine Kinase (SYK) is Necessary for cGAS-STING Signaling in Müller Glia and Visual Function Deficits in Diabetic Mice. (from Ophthalmology/diabetic retinopathy)
Yerlikaya Esma I; Sunilkumar Siddharth; Subrahmanian Sandeep M; Toro Allyson L; * — 2026
Score: 6/10* | Pathways: cGAS-STING, VDAC1, NLRP3, IRF7-metabolic, treatment-target, other

This paper directly demonstrates that mitochondrial membrane permeability → cytosolic mtDNA → cGAS-STING → NF-κB/IL-1β/CCL2 signaling axis (core BLUE pathway) operates in a glial cell context under metabolic stress, and introduces SYK as a novel upstream kinase required for cGAS-STING activation, representing a potential druggable node in the same pathway that drives the SAMHD1 interferonopathy syndrome.
DOI: 10.1002/glia.70155

Irradiated Liver Cancer Cell Vaccine Transfected With GM-CSF Induces Specific and Long-Lasting Anti-tumour Immunity Through the Synergistic Effect of Oxidised mtDNA and GM-CSF. (from Oncology/hepatology)
Song Zhiruo; Jiang Yujie; Zhang Yu; Ao Danyi; Ye Chunjun — 2026
Score: 6/10 | Pathways: cGAS-STING, POLG-mtDNA, other

This paper directly demonstrates that irradiation-induced oxidized mtDNA (ox-mtDNA) activates cGAS-STING signaling to drive DC maturation and anti-tumor immunity, mechanistically paralleling the BLUE pathway in which SAMHD1/VDAC1 interaction loss permits cytosolic mtDNA fragments to activate cGAS-cGAMP-STING-IRF3-IFN-I, and also invokes oxidized mtDNA as the NLRP3 activator central to Loop B, but the clinical context (liver cancer vaccine) and therapeutic goal (immune activation) are the opposite of the disease mechanism being surveilled.
DOI: 10.1111/cpr.70198

Clotting the Gap Between Mitochondria-Mediated Immunity and Mitochondrial Transfer. (from Hematology/Transfusion medicine)
Tupin Florian; Gonzalez-Chapa Jorge A; Chung Jay H; Lood Christian; Boilard Eric — 2026
Score: 6/10 | Pathways: cGAS-STING, VDAC1, NLRP3, POLG-mtDNA, ME-CFS, clinical-phenotype, other

This review directly covers mtDNA release through mitochondrial pores (VDAC1-relevant) triggering innate immune responses via cGAS-STING, which is the BLUE stream of the SAMHD1 mechanism, and additionally addresses extracellular mitochondria as DAMPs in autoimmune and cardiovascular contexts relevant to the family phenotype, though the platelet-centric framing is adjacent rather than mechanistically central to SAMHD1 haploinsufficiency.
DOI: 10.1161/circresaha.125.326987

Puerarin alleviates crystalline silica-induced pulmonary fibrosis by suppressing mtDNA leakage-induced senescence and EMT in alveolar type II cells. (from Pulmonology / occupational medicine)
Gong Shuwen; Su Wei; Wei Xiaoxi; Ma Xinyu; Cao Anqi — 2026
Score: 6/10 | Pathways: cGAS-STING, POLG-mtDNA, other

This paper directly demonstrates the mtDNA leakage → cGAS-STING activation axis (the BLUE stream) as a pathological mechanism driving cellular senescence and fibrosis, and shows pharmacological suppression of mtDNA transcription/replication attenuates this — mechanistically parallel to how SAMHD1 haploinsufficiency-driven cytosolic mtDNA fragments activate cGAS-STING in the disease model, though the disease context (silicosis/pulmonary fibrosis) is unrelated to SAMHD1.
DOI: 10.1016/j.ecoenv.2026.120127

Rethinking Mitochondria: The Extracellular Dimension. (from Cardiovascular biology / mitochondrial cell biology)
Pena-Couso Laura; Makuch Magdalena; Nicolas-Avila Jose Angel — 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, ME-CFS, other

This review directly addresses extracellular release of mtDNA and mitochondrial components—the core upstream trigger of cGAS-STING and NLRP3 activation in the BLUE and PURPLE pathways—including VDAC1-mediated release mechanisms and the inflammatory signaling consequences, making it highly relevant to the mtDNA escape loops central to SAMHD1 haploinsufficiency pathophysiology, though SAMHD1 itself is not mentioned.
DOI: 10.1161/circresaha.125.326988

Programmable DNAzyme nanocatalysts orchestrate redox-immune coupling for time-gated cancer immunomodulation. (from Nanomedicine/cancer immunotherapy)
Wang Lu; Luo Rongping; Zou Lingxiu; Liu Xiaojing; Tang Zhuojia — 2026
Score: 5/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, other

This paper mechanistically recapitulates the BLUE stream (cytosolic mtDNA release → cGAS-STING → type I IFN) as a deliberate engineered outcome in cancer immunotherapy, confirming that mitochondrial membrane depolarization and mtDNA leakage are sufficient to drive robust cGAS-STING/IFN-I activation—directly analogous to the proposed VDAC1 macropore mechanism in SAMHD1 haploinsufficiency—but is entirely in an oncology/nanomedicine context with no direct relevance to SAMHD1, haploinsufficiency, or the family phenotype.
DOI: 10.1186/s12951-026-04397-z

Mitochondria-Derived Vesicles and Mitochondrial Extracellular Vesicles in Health and Cardiovascular Disease. (from Cardiology/mitochondrial biology)
Rapushi Erjola; Aryal Anubhav; Yang Tianyuan; Li Zhixin; Wang Xiaohong — 2026
Score: 5/10 | Pathways: VDAC1, POLG-mtDNA, cGAS-STING, NLRP3, ISG15-mitophagy, mTOR-lysosomal, other

MDVs and mitoEVs represent quality control mechanisms that intersect directly with the disease model's core loops—oxidized/damaged mtDNA packaging in MDVs touches POLG-mtDNA and cGAS-STING axes, mitoEV-released mtDNA fragments are a known cGAS ligand, and the endolysosomal/autophagy flux discussed is directly impaired by ISGylation of BECN1 in the RED pathway—but the paper does not address SAMHD1, interferonopathy, or the specific haploinsufficiency mechanism, making it an indirect mechanistic background reference rather than a direct pathway paper.
DOI: 10.1161/circresaha.125.327357

🟢 Low Relevance (Score 3–4)

Potential specialty bridges — skim titles

Multi-Ion Channel Nanomedicines Targeting Zinc Transporter 1/ATPase Copper Transporters Disrupt Copper/Iron Homeostasis to Enhance Tumor Immunotherapy. (from Oncology/Nanomedicine)
Ma Guangyu; Li Yuting; Li Xiang; Yu Dehong; Chao Minghao — 2026
Score: 4/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, other

The paper activates cGAS-STING via mtDNA release from mitochondrial disruption (tangentially overlapping with the BLUE stream), but the context is tumor-targeted nanomedicine using cuproptosis/ferroptosis with no connection to SAMHD1, interferonopathy, haploinsufficiency, or any family phenotype.
DOI: 10.1021/acsnano.6c00358

Immune signaling and function in neurodegeneration. (from neurology/neuroimmunology)
Latour Yvonne L; McGavern Dorian B — 2026
Score: 3/10 | Pathways: cGAS-STING, NLRP3, JAK-STAT, ME-CFS, other

This review broadly covers innate and adaptive immune signaling in neurodegeneration, touching on cGAS-STING, NLRP3, and microglial pattern recognition receptors that overlap with the interferonopathy/NLRP3 pathways central to SAMHD1 haploinsufficiency, but it does not address SAMHD1, dNTPase function, mitochondrial mechanisms, ISG15/mitophagy, or the specific AGS-spectrum interferonopathy relevant to this disease profile, making the connection tangential.
DOI: 10.1172/jci199850

Oxidative stress in neurodegeneration: from a simple insult to a dynamic regulator. (from Neurology/Neuroscience)
Zhang Lan; Zhai Xinyue; Yan Yalong; Xiang Lihong; Zhang Yue — 2026
Score: 3/10 | Pathways: POLG-mtDNA, mTOR-lysosomal, NLRP3, other

This broad review covers oxidative stress, mitochondrial quality control, mTOR, and NLRP3-adjacent ferroptosis/NETosis pathways that are tangentially relevant to the SAMHD1 interferon-mitochondrial syndrome, but lacks any specific focus on cGAS-STING, VDAC1, ISG15, SAMHD1, or interferonopathy mechanisms, making its connection to the disease profile indirect and general.
DOI: 10.1080/13510002.2026.2654906

Jieduquyuziyin prescription for systemic lupus erythematosus: a system-level therapeutic strategy for immunological recalibration. (from Traditional Chinese Medicine / Integrative Medicine)
Gan Yihong; Liu Jingqun; Zhou Shihui; Lin Ke; Wang Xinchang — 2026
Score: 3/10 | Pathways: JAK-STAT, mTOR-lysosomal, NLRP3, IRF7-metabolic, other

This review covers SLE immunopathology with some overlapping pathways (NF-κB, mTOR/AKT, mitochondrial dysfunction, metabolic reprogramming, Bim upregulation) but focuses entirely on a Traditional Chinese Medicine herbal formula and does not engage with SAMHD1, cGAS-STING, VDAC1, ISG15, or type I interferonopathy mechanisms that are central to the disease profile.
DOI: 10.1186/s13020-026-01397-x

The oxidative stress paradigm in arbovirus infections: mechanisms and therapeutic insights. (from Virology/Infectious Disease)
Ke Yee Chang; Lani Rafidah; Hassandarvish Pouya — 2026
Score: 3/10 | Pathways: NLRP3, ME-CFS, other

This review covers arbovirus-induced oxidative stress and NF-κB/mitochondrial dysfunction, touching tangentially on ROS-driven inflammatory cascades (including NF-κB and mitochondrial impairment) relevant to the interferon-mitochondrial syndrome, but does not address SAMHD1, cGAS-STING, NLRP3 inflammasome activation, ISG15-mitophagy, or any of the core mechanistic pathways in the disease profile, making its connection indirect and non-specific.
DOI: 10.1080/13510002.2026.2659994

Pathway Coverage This Week

cGAS-STING: 15 papers
other: 15 papers
POLG-mtDNA: 14 papers
VDAC1: 10 papers
NLRP3: 10 papers
ISG15-mitophagy: 5 papers
treatment-target: 5 papers
ME-CFS: 4 papers
JAK-STAT: 3 papers
mTOR-lysosomal: 3 papers
clinical-phenotype: 2 papers
IRF7-metabolic: 2 papers

↩ Re-run 02:23 UTC | Model: claude-sonnet-4-6

Summary: 20 new papers | 16 high-relevance (≥7) | 1 medium (5–6) | 3 low (3–4)

🔴 High Relevance

Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity. (from Metabolism/Hepatology (metabolic dysfunction-associated steatohepatitis, insulin resistance, obesity))
Danhui Liu; Chuanli Zhou; Xiaochen Wang; Zhou Luo; Ruiyao Xu — Science 2026
Score: 9/10 | Pathways: NLRP3, dNTPase, POLG-mtDNA, VDAC1, ME-CFS, treatment-target, clinical-phenotype, IRF7-metabolic

This paper directly demonstrates the SAMHD1 → dNTP accumulation → mitochondrial dNTP transport → oxidized mtDNA → NLRP3 hyperactivation → IL-1β axis (the PURPLE pathway) in macrophages across zebrafish, mice, and humans, and shows that SAMHD1 loss phenocopies the exact mechanism proposed for the A565T haploinsufficiency variant, with the additional translational finding that blocking mitochondrial dNTP transport rescues NLRP3 hyperactivation—directly supporting mechanistic and therapeutic hypotheses for this family.
DOI: 10.1126/science.adq9006

Targeting VDAC1-dependent mtDNA release attenuates fibroblast innate immune activation and vitiligo pathogenesis. (from Dermatology)
Jinpeng Lv; Huansha Zhang; Wenhao Yu; Peiwen Jiang; Chuanwei Yin — International immunopharmacology 2026
Score: 8/10 | Pathways: cGAS-STING, NLRP3, VDAC1, poliosis-neural-crest, treatment-target, clinical-phenotype

This paper directly demonstrates the VDAC1 oligomerization → mtDNA efflux → cGAS-STING + NLRP3 activation axis in dermal fibroblasts—the precise BLUE-stream mechanism proposed for SAMHD1 haploinsufficiency—while also linking this to melanocyte destruction and depigmentation (poliosis/piebaldism phenotype in the family), and validating VBIT-4 as a therapeutic intervention that rescues repigmentation in vivo.
DOI: 10.1016/j.intimp.2026.116411

Zinc protects against neuroinflammation after spinal cord injury by regulating mitophagy-dependent mtDNA-cGAS-STING signaling. (from Neurotrauma/spinal cord injury)
Feng Jin; Zengtao Song; Yu Deng; Hongkai Yang; Yajiang Yuan — Free radical biology & medicine 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, ISG15-mitophagy, POLG-mtDNA, treatment-target

This paper directly demonstrates the VDAC1→mtDNA leakage→cGAS-STING axis and PINK1-Parkin mitophagy block as convergent pathways, precisely mirroring the BLUE and RED streams of the SAMHD1 A565T mechanism, and identifies zinc as a therapeutic modulator of this circuit with mechanistic data on BAX/BAK/VDAC1 regulation of mtDNA cytosolic release.
DOI: 10.1016/j.freeradbiomed.2026.02.010

PGAM1-dependent VDAC1 oligomerization disrupts mitochondrial quality control to drive doxorubicin cardiotoxicity via the cGAS-STING-ferroptosis axis. (from Cardiology/oncology (doxorubicin cardiotoxicity))
Yukun Li; Sicheng Zheng; Haowen Zhuang; Ji Wu; Junyan Wang — Free radical biology & medicine 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, ISG15-mitophagy, POLG-mtDNA, treatment-target, clinical-phenotype

This paper directly demonstrates the VDAC1 oligomerization → cytosolic mtDNA leakage → cGAS-STING activation axis in cardiomyocytes with mechanistic detail highly relevant to the BLUE and RED streams of the SAMHD1 haploinsufficiency model, additionally linking this pathway to ferroptosis and disrupted mitochondrial quality control (mitophagy collapse), while identifying PGAM1 as a novel upstream regulator of VDAC1 macropore formation and providing pharmacological validation points applicable to cardiac manifestations of the interferonopathy.
DOI: 10.1016/j.freeradbiomed.2026.01.065

Mitochondrial DNA release via VDAC1 in keratinocytes: a key driver of innate immunity and vitiligo pathogenesis (from Dermatology)
Jinpeng Lv; Wenhui Xu; Peiwen Jiang; Wenhao Yu; Hui Xue — Cell Death & Disease 2026
Score: 8/10 | Pathways: cGAS-STING, NLRP3, VDAC1, poliosis-neural-crest, treatment-target, other

This paper directly demonstrates the BLUE-stream mechanism (VDAC1 oligomerization → cytosolic mtDNA → cGAS-STING + NLRP3 co-activation → type I interferon + pyroptosis) in a pigmentation disorder context, and validates VBIT-4 as a therapeutic VDAC1 inhibitor that blocks the entire cascade, while the vitiligo/depigmentation phenotype directly parallels the poliosis/piebaldism neural-crest pigmentation phenotype tracked in the SAMHD1 A565T family.
DOI: 10.1038/s41419-026-08585-5

Mitochondrial transfer from immune to tumor cells enables lymph node metastasis. (from Oncology/Cancer Biology)
Azusa Terasaki; Keshav Bhatnagar; Alexis T. Weiner; Yuhao Tan; Viktoria Szeifert — Cell metabolism 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, ISG15-mitophagy, JAK-STAT, BIK-cancer, POLG-mtDNA, treatment-target

This paper directly demonstrates the mechanistic loop central to the disease model: exogenous mtDNA leaking into the cytosol activates cGAS/STING → type I interferon signaling, mirroring the BLUE stream (VDAC1 macropore → cytosolic mtDNA → cGAS → IFN-I), while also implicating mitochondrial transfer and fusion dynamics relevant to MFN1/MFN2 and mitophagy blocks; additionally, the cancer metastasis context (lymph node colonization, immune evasion via IFN-I) is directly relevant to the family's oncological phenotypes (multiple myeloma, prostate, endometrial, duodenal cancers) and validates cGAS, STING, and type I interferon as actionable treatment targets in this pathway.
DOI: 10.1016/j.cmet.2025.12.014

Mitochondrial DNA: A Key Alarmin Igniting the Inflammasome Fire in Health and Disease. (from Mitochondrial biology)
W. Park — Immunology 2026
Score: 8/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, urate-NLRP3, ME-CFS, treatment-target

This review directly covers the mtDNA-NLRP3/cGAS-STING inflammasome axis—including ox-mtDNA as NLRP3 ligand, mPTP/VDAC1-mediated mtDNA release, and cGAS-STING amplification—which maps precisely onto the PURPLE and BLUE mechanistic streams of SAMHD1 haploinsufficiency pathology, and discusses therapeutic targets (MCC950, cGAS-STING inhibitors) directly relevant to treatment strategy.
DOI: 10.1111/imm.70111

Abstract 3273: The mitochondrial protease YME1L regulates type 1 interferon signaling via the STING pathway in AML (from Oncology/Hematology)
Yihe Zhang; G. Thomas; R. Hurren; Yongran Yan; M. Gronda — Cancer Research 2026
Score: 8/10 | Pathways: cGAS-STING, ISG15-mitophagy, JAK-STAT, POLG-mtDNA, BIK-cancer, other

This paper directly demonstrates that mitochondrial proteostasis disruption triggers cytosolic dsDNA accumulation → cGAS-STING activation → IFN-β/ISG15/IFIT2 upregulation in AML, mechanistically paralleling the BLUE and RED streams of the SAMHD1 A565T disease model (VDAC1/mtDNA escape → cGAS-STING → IFN-I → ISG15), while also being relevant to the family's hematologic malignancy phenotype (multiple myeloma cluster) and SAMHD1's known role as a tumor suppressor in AML.
DOI: 10.1158/1538-7445.am2026-3273

Targeting Mitochondrial Permeability and Cytosolic mtDNA Release: Astragaloside IV Suppresses cGAS-STING Signaling Pathway to Protect against Cadmium-induced Hepatotoxicity. (from Hepatotoxicology/environmental medicine)
Hao Xu; Jingyi Yang; Yu Zhang; Shihui Li; Ziwei Wang — Free radical biology & medicine 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, treatment-target

This paper directly demonstrates the mechanistic axis most central to the BLUE stream of the disease model—mitochondrial permeability leading to cytosolic mtDNA release activating cGAS-STING innate immune signaling in a hepatic context—and identifies AS-IV as a suppressor of this pathway, providing both mechanistic validation and a potential therapeutic candidate relevant to the interferonopathy component of SAMHD1 haploinsufficiency.
DOI: 10.1016/j.freeradbiomed.2026.01.027

Fumarate loss destabilizes mitochondria and activates cGAS-STING in OLP. (from Oral medicine / mucosal immunology)
Yan Hu; Huyan Chen; Chenyun Ding; Sheng Zhang; Qing Chen — Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, VDAC1, IRF7-metabolic, treatment-target

This paper directly demonstrates the mtDNA leakage → cytosolic mtDNA → cGAS-STING → TBK1-IRF3-NF-κB axis driven by mitochondrial metabolic dysfunction (TCA imbalance), closely mirroring the BLUE stream mechanism in SAMHD1 haploinsufficiency where VDAC1 macropore formation releases mtDNA fragments to activate cGAS-STING, and additionally validates monomethyl fumarate as a pharmacological intervention that restores mitochondrial homeostasis and suppresses innate immune activation—offering a novel treatment target concept relevant to the interferon-mitochondrial syndrome.
DOI: 10.1016/j.biopha.2026.119127

DNMT1 knockdown mitigates sepsis-induced myocardial dysfunction by preventing TFAM-mediated mitochondrial DNA cytosolic escape and subsequent cGAS-STING to regulate macrophage M2 polarization. (from Cardiology/critical care)
Min Li; Yang Liu; Kuo Qu; Yu Zhang; Hailing Yang — Biochemical pharmacology 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, treatment-target, clinical-phenotype

This paper directly demonstrates the mtDNA cytosolic escape → cGAS-STING activation axis in a cardiac context, with TFAM as a regulator of mitochondrial integrity preventing mtDNA release — mechanistically parallel to the BLUE stream (VDAC1 macropore → cytosolic mtDNA → cGAS → STING → IFN-I) in the SAMHD1 haploinsufficiency model, and the cardiology clinical context (interferonopathy + mitochondrial cardiomyopathy) is directly relevant to the family phenotype tracking.
DOI: 10.1016/j.bcp.2026.117709

Neuronal TLR4 upregulation activates the cGAS-STING pathway to induce ferroptosis in EAE mice. (from Neurology/neuroimmunology (MS/EAE model))
H. Qin; Lingfei Yang; Jing Du; XiaoMeng Xu; Ziyi Chen — International immunopharmacology 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, treatment-target, other

This paper directly demonstrates a TLR4-mtDNA cytosolic release → cGAS-STING signaling cascade in neurons, mechanistically overlapping with the BLUE stream (VDAC1 macropore → cytosolic mtDNA fragments → cGAS-STING → IFN-I) of the SAMHD1 haploinsufficiency model, and introduces ferroptosis/NCOA4-ferritinophagy as a downstream consequence with Liproxstatin-1 as a potential therapeutic target, offering novel mechanistic and treatment implications relevant to neurological manifestations (ASD/ADHD/dystonia) in the disease profile.
DOI: 10.1016/j.intimp.2026.116364

Selective antagonism of adenosine A2A receptor reduces hypobaric hypoxia-induced neuroinflammation by inhibiting cGAS-STING pathway (from Neurology/hypoxia medicine)
Hongbo Cheng; Yehui Gao; Huiying Shang; Weiye Han; Xiaotong Zhang — Scientific Reports 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, treatment-target, other

This paper directly demonstrates the mechanistic chain: ADORA2A activation → cAMP → EPAC1 → VDAC1 upregulation → MPTP opening → cytosolic mtDNA release → cGAS-STING activation → neuroinflammation, which maps precisely onto the BLUE pathway (VDAC1 macropore → mtDNA → cGAS-STING) central to the SAMHD1 A565T mechanism, and identifies ADORA2A antagonism as a tractable pharmacological intervention to suppress this axis.
DOI: 10.1038/s41598-025-30717-8

Macrophage TRIM21 Inhibition Ameliorates Murine Acute Pancreatitis via PHB2‐Mediated Mitochondrial Stabilization (from Gastroenterology/Pancreatology)
Yansong Xu; Yuansong Sun; Xin Zhou; Kai Song; Chunlin Yin — Advanced Science 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, NLRP3, ISG15-mitophagy, treatment-target, other

This paper directly demonstrates a TRIM21→K11-ubiquitination→PHB2 degradation→impaired mitophagy→cytosolic mtDNA accumulation→cGAS-STING activation cascade, which maps precisely onto the BLUE and RED streams of the disease mechanism (VDAC1/mtDNA escape→cGAS→STING→IFN-I and the ISGylation-mitophagy block), and notably ANKIB1/K11-ubiquitin is a named molecular player in the disease profile, making TRIM21's K11-linked ubiquitination activity directly relevant to interferonopathy amplitude control.
DOI: 10.1002/advs.202517877

Abstract 5598: Exploiting electron transport chain dynamics to sensitize OXPHOS-dependent cancers to immunotherapy (from Oncology/Cancer Biology)
Haojie Dong; Guoyun Kao; Umesh Yadav; Lei Zhang; Arshad J. Ansari — Cancer Research 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, VDAC1, JAK-STAT, BIK-cancer, treatment-target

This paper directly demonstrates a novel mechanism by which mitochondrial ETC dysfunction causes mtDNA leakage into the cytosol activating cGAS-STING-IFN-I signaling in AML—highly parallel to the BLUE stream in SAMHD1 haploinsufficiency where VDAC1 macropore releases mtDNA to activate cGAS, with DHODH/SDH inhibition as a pharmacological tool that recapitulates the mitochondrial redox/mtDNA instability axis relevant to the family's hematologic malignancy phenotype (multiple myeloma) and the core interferonopathy mechanism.
DOI: 10.1158/1538-7445.am2026-5598

TRIM25 triggers pyroptosis through mitochondrial DNA release in intestinal ischemia-reperfusion injury. (from Gastroenterology/surgery (intestinal ischemia-reperfusion))
Song Yao; Xiaolong Lu; Ximeng Ren; Meng Li; Fanrui Meng — Free radical biology & medicine 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA

This paper demonstrates a mechanistic axis—mitochondrial outer membrane permeabilization → cytosolic mtDNA release → cGAS-STING activation → NLRP3 inflammasome pyroptosis—that maps directly onto the BLUE and PURPLE loops of the SAMHD1 haploinsufficiency model, with the novel TRIM25/PGAM5/mtDNA node offering a parallel upstream mechanism to VDAC1 macropore-mediated mtDNA escape, and the cGAS inhibitor intervention directly validating a therapeutic target relevant to the disease.
DOI: 10.1016/j.freeradbiomed.2026.02.019

🟡 Medium Relevance

Nanomedicine leverages cuproptosis-mediated cGAS-STING activation to enhance antitumor immunity (from Oncology/Nanomedicine)
Chunfei Li; Yunze Li; Zhiji Wang; Yumin Wang; Wenzheng Guan — Journal of Nanobiotechnology 2026
Score: 6/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, treatment-target, other

This paper directly addresses the cuproptosis→mitochondrial damage→mtDNA cytosolic release→cGAS-STING→type I interferon axis in a cancer immunotherapy context, which maps closely to the BLUE stream of the disease mechanism (VDAC1 macropore→cytosolic mtDNA→cGAS-STING→IFN-I), and the mtDNA-cGAS-STING connection is mechanistically identical to what drives interferonopathy in SAMHD1 haploinsufficiency, though the paper is cancer-focused and does not address SAMHD1, haploinsufficiency, or the chronic low-grade interferonopathy phenotype.
DOI: 10.1186/s12951-026-04203-w

🟢 Low Relevance

Haploinsufficiency of MBD5 and MBD6 impairs mitochondrial respiration through chromatin-mediated gene regulation. (from epigenetics/neurodevelopment)
Makiko Meguro-Horike; Keiko Iwata; H. Matsuzaki; Shin-ichi Horike — Biochemical and biophysical research communications 2026
Score: 4/10 | Pathways: ME-CFS, other, clinical-phenotype

This paper demonstrates that haploinsufficiency (heterozygous loss) of chromatin regulators causes mitochondrial respiratory dysfunction and a compensatory glycolytic shift in a neuronal ASD model, which is tangentially relevant as a parallel haploinsufficiency-mitochondria-ASD axis, but involves no shared molecular players (cGAS, STING, NLRP3, SAMHD1, interferon, dNTP pool) with the SAMHD1 A565T mechanism.
DOI: 10.1016/j.bbrc.2026.153288

Mitochondria and Lipid Defects in Hereditary Progranulin-Related Frontotemporal Dementia (from Neurology/neurodegeneration)
Jon Ondaro; Jose Luis Zúñiga-Elizari; Mónica Zufiría; Maddi Garciandia-Arcelus; * — Cells 2026
Score: 4/10* | Pathways: mTOR-lysosomal, POLG-mtDNA, other

This paper examines GRN haploinsufficiency causing lysosomal dysfunction, mitochondrial swelling/decreased respiration, and lipid droplet accumulation — sharing the haploinsufficiency mechanism and mitochondrial-lysosomal axis with SAMHD1 disease, but through a completely distinct gene and neurodegenerative context with no direct connection to cGAS-STING, NLRP3, ISG15, or the interferon-mitochondrial loops central to SAMHD1 p.A565T pathology.
DOI: 10.3390/cells15030276

AAVrh74.tMCK.NT-3 Surrogate Gene Therapy in a Mouse Model of CMT2A. (from Neuromuscular disease / gene therapy)
B. Ozes; Lingying Tong; Kyle Moss; M. Myers; Israel Ndengabaganizi — International journal of molecular sciences 2026
Score: 4/10 | Pathways: ISG15-mitophagy, POLG-mtDNA, other

The paper focuses on MFN2 haploinsufficiency and NT-3 gene therapy in CMT2A, touching on mitofusin biology (MFN2 is ISGylated in the RED pathway blocking mitophagy) and mitochondrial abnormalities, but the mechanistic context is peripheral neuropathy/Schwann cell biology rather than the interferonopathy-mitochondrial axis central to SAMHD1 A565T, making the connection indirect and tangential.
DOI: 10.3390/ijms27041942

↩ Re-run 06:58 UTC | Model: claude-sonnet-4-6

Summary: 30 new papers | 16 high-relevance (≥7) | 10 medium (5–6) | 4 low (3–4)

🔴 High Relevance

STING causes replication stress and nascent DNA degradation via SAMHD1 (from Cancer biology / DNA replication / genome stability)
Barbara Teodoro-Castro; Rafael Cançado de Faria; Elena V Shashkova; Atika Maliqu — bioRxiv 2026
Score: 9/10 | Pathways: cGAS-STING, dNTPase, POLG-mtDNA, ME-CFS, AGS-spectrum, treatment-target, other

This paper directly demonstrates a STING–SAMHD1 axis in which nuclear STING activates SAMHD1's dNTPase activity to deplete dNTPs, slow/stall replication forks, and promote MRE11-mediated nascent DNA degradation—mechanistically inverting and extending the core disease model where SAMHD1 haploinsufficiency causes dNTP pool expansion, and showing that STING-driven SAMHD1 hyperactivation produces the same genome instability and replication stress phenotype, directly validating the STING↔SAMHD1 bidirectional relationship central to the surveillance disease.
DOI: 10.64898/2026.03.28.714577

Linking mitochondrial DNA release to neurodegeneration and cognitive decline. (from Neuroscience/neurodegeneration)
Z. Fang; C. Barbosa; Daniela Marinho; Rita Peixoto; I. Ferreira — Ageing research reviews 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy, POLG-mtDNA, mTOR-lysosomal, ME-CFS, other

This review directly addresses the BLUE and RED pathway mechanisms central to the disease model—mtDNA escape via VDAC1/mitochondria-derived vesicles activating cGAS-STING, impaired mitophagy (BECN1/Parkin) allowing damaged mtDNA accumulation, and the resulting innate immune neuroinflammation—providing a mechanistic synthesis highly relevant to the SAMHD1 interferonopathy's neurological and cognitive phenotypes including AuDHD and ME/CFS.
DOI: 10.1016/j.arr.2026.103062

Mitochondrial DNA: a molecular switch driving sterile neuroinflammation (from Neurology/Neurodegeneration)
A. Jauhari; Tanisha Singh; D. Carlisle; Robert M. Friedlander — Translational Neurodegeneration 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, NLRP3, ME-CFS, AGS-spectrum

This review directly covers the BLUE pathway mechanism (mtDNA escape → cGAS-STING → type I interferon) and POLG-mtDNA damage, providing neuroinflammation context highly relevant to the SAMHD1/VDAC1 interaction loss and cytosolic mtDNA fragment signaling central to this disease model, though it does not address SAMHD1 specifically.
DOI: 10.1186/s40035-026-00540-w

The human antibacterial factor APOL3 couples lysosomal damage to mitochondrial DNA efflux and type I IFN induction. (from Microbiology/innate immunity (antibacterial factor repurposed as endogenous danger amplifier))
Dominic A. Ritacco; Hamna Shahnawaz; Antonia Oduguwa; Jacob Hawk; B. Vizcaino — Molecular cell 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, mTOR-lysosomal, ISG15-mitophagy, JAK-STAT

This paper directly elucidates a novel IFN-γ-inducible pathway (APOL3) connecting lysosomal damage → sub-lethal MOMP (BAK/BAX macropores, analogous to VDAC1 macropores in the BLUE stream) → IMM permeabilization via cardiolipin solubilization → mtDNA efflux → cGAS-STING → type I IFN, providing a mechanistically parallel and amplifying route for the SAMHD1 A565T interferonopathy loop where lysosomal failure (mTOR-lysosomal axis, BECN1 ISGylation block) and mitochondrial outer membrane events converge to feed cytosolic mtDNA and sustain cGAS activation.
DOI: 10.1016/j.molcel.2026.01.029

Mitochondrial DNA Instability and Neuroinflammation: Connecting the Dots Between Base Excision Repair and Neurodegenerative Disease (from Neuroscience/DNA repair biology)
Magan N Pittman; Mary Beth Nelsen; Marlo K. Thompson; Aishwarya Prakash — Genes 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, ME-CFS, treatment-target, other

This review directly addresses the mechanistic chain central to the SAMHD1 A565T syndrome: mtDNA instability (via oxidative damage and impaired BER) → mtDNA fragment escape into cytosol → DAMP-driven cGAS-STING and NLRP3 inflammasome activation → neuroinflammation, mirroring the PURPLE and BLUE pathway loops, with therapeutic strategies targeting mtDNA repair and neuroimmune modulation that are directly actionable for this condition.
DOI: 10.3390/genes17010082

The cGAS-STING pathway at the crossroads of neuroimmunology: bridging innate immunity to aging and neurodegeneration (from Neurology/Neuroimmunology)
Zheng Wu; Rong-Jun Jia; Qi Zhang; Li-Yan Huang; Junyang Yan — Biomarker Research 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, VDAC1, JAK-STAT, AGS-spectrum, ME-CFS, treatment-target

This review directly covers the BLUE stream (cGAS→cGAMP→STING→IRF3→IFN-I) including mtDNA escape mechanisms and mitochondrial DNA as a cGAS activator, with explicit coverage of cGAS/STING inhibitors as therapeutic targets, all central to the SAMHD1 haploinsufficiency mechanism—though SAMHD1 itself is not mentioned, the neurological context (ASD/ADHD phenotypes, neuroinflammation, aging) maps onto the family's neurodevelopmental and ME/CFS phenotypes.
DOI: 10.1186/s40364-026-00906-2

NLRP10 engages oxidized DNA through a Schiff-base mechanism and dissociates from NLRP3 upon inflammasome activation (from Structural/biochemical biology)
J. Cabral; Angela Lackner; Wenjin Jiang; Sophia Lin; Haitian Zhou — Communications Biology 2026
Score: 7/10 | Pathways: NLRP3, POLG-mtDNA, cGAS-STING, ME-CFS, treatment-target, other

This paper directly addresses the PURPLE stream mechanism—oxidized mtDNA (8-OHdG/D-loop) release into the cytosol triggering NLRP3 inflammasome—and introduces NLRP10 as a novel modulator that cleaves oxidized mtDNA via Schiff-base chemistry and dissociates from NLRP3 upon activation, providing a new regulatory node and potential therapeutic target (glycosylase inhibitors) within the exact mitochondrial-NLRP3 axis central to the SAMHD1 A565T disease model.
DOI: 10.1038/s42003-025-09501-x

Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer’s disease pathogenesis (from Neuroscience/Alzheimer's disease)
Yongqing Liu; Minghua Fan; Yingzhi Ye; Henry Yi Cheng; Shuying Sun — bioRxiv 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, POLG-mtDNA, dNTPase, treatment-target

This paper directly demonstrates that cytosolic mtDNA release drives cGAS-STING and NLRP3 activation in microglia via CMPK2-mediated mtDNA synthesis regulation — mechanistically parallel to the SAMHD1 haploinsufficiency model where dNTP pool expansion (especially dGTP) perturbs mtDNA replication and triggers the same cGAS-STING/NLRP3 inflammatory loops, with KAT7 inhibition representing a novel epigenetic therapeutic entry point into these shared pathways.
DOI: 10.64898/2026.02.19.706884

Therapeutic Targeting of the Mitochondrial Dysfunction-PANoptosis Axis: Mechanistic Insights and Emerging Strategies. (from Cell biology / translational medicine)
Arpit Sharma; Shruti S Raut; Alok Shukla; Amit Singh; Abha Mishra — Translational research : the journal of laboratory and clinical medicine 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy, POLG-mtDNA, treatment-target, other

This review directly covers the cytosolic mtDNA→cGAS-STING→inflammasome→PANoptosome axis and mitophagy failure as upstream drivers of inflammatory cell death, mapping closely onto the BLUE (cGAS-STING), PURPLE (ox-mtDNA/NLRP3), and RED (mitophagy block) streams of the SAMHD1 A565T mechanism, with therapeutic targeting implications for NLRP3, cGAS-STING, and mitochondrial dynamics.
DOI: 10.1016/j.trsl.2026.03.004

The importance of mitochondria and mitochondrial calcium signaling in health and disease: an updated outlook on inflammation (from Translational medicine / mitochondrial biology)
G. Morciano; Giulia Pellielo; Esther Densu Agyapong; C. Pellegrino; S. Patergnan — Journal of Translational Medicine 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, ISG15-mitophagy, treatment-target, other

This review comprehensively covers mitochondrial DAMPs (mtDNA, ROS, cardiolipin, ATP) activating innate immune receptors and inflammasomes including NLRP3, mtDNA escape via membrane permeabilization (directly relevant to VDAC1 macropore and cGAS-STING activation), mitochondrial calcium dysregulation amplifying ROS and membrane permeabilization, and emerging therapeutic strategies (mitochondrial biogenesis restoration, Ca2+ flux modulators, antioxidants) that directly map to the PURPLE, BLUE, and RED mechanistic streams of SAMHD1 haploinsufficiency pathology.
DOI: 10.1186/s12967-026-07783-1

Immune remodeling via mitochondria-dependent STING activation enhances cabozantinib response in hepatocellular carcinoma (from Oncology/Hepatology)
P. Rider; A. Tutusaus; Carlos Cuño-Gómiz; Flavia Savino; Aida Marsal — Journal of Experimental & Clinical Cancer Research : CR 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, JAK-STAT, treatment-target, BIK-cancer, other

This paper directly demonstrates the mechanistic axis central to the SAMHD1 syndrome—mitochondrial stress → cytosolic mtDNA release → cGAS/STING activation → ISG upregulation—and validates it in a clinically actionable hepatocellular carcinoma context with in vivo and patient proteomic data, providing novel therapeutic implications (STING agonism) relevant to the BLUE and RED pathway loops, though SAMHD1 itself is not studied.
DOI: 10.1186/s13046-025-03632-z

cGAS-STING activation in Parkinson's Disease: From mechanisms to Disease-Modifying therapeutic strategies. (from Neurology/Neurodegeneration)
Jemimol Solomon; S. Mandal; K. Aran — Gene 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, NLRP3, ISG15-mitophagy, JAK-STAT, treatment-target, other

This paper directly covers the BLUE stream (cGAS→STING→IRF3→IFN-I) and RED stream (IFN-I→mitophagy block) as they operate in a neuronal context, with mitochondrial dysfunction as the upstream trigger of cytosolic mtDNA release—mechanistically identical to the SAMHD1/VDAC1 haploinsufficiency model—and discusses disease-modifying strategies targeting cGAS-STING that are directly translatable to the SAMHD1 interferonopathy therapeutic framework, though SAMHD1 itself is not mentioned.
DOI: 10.1016/j.gene.2026.150000

Kidney‐Targeted Nanoparticles with ROS Scavenging and STING Inhibition for the Treatment of Acute Kidney Injury (from Nephrology/Nanomedicine)
Tianying Xing; Meifang Shen; Xiangxin Zeng; Xin Cui; Tiejun Bing — Advanced Functional Materials 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, treatment-target, other

This paper directly demonstrates that mitochondrial DNA release activates cGAS-STING signaling driving pathological inflammation, validates STING as a therapeutic target, and tests a pharmacological STING antagonist (H-151) plus ROS scavenging in vivo — directly relevant to the BLUE stream mechanism (VDAC1 macropore → cytosolic mtDNA → cGAS → STING → IFN-I) central to this disease, and identifies treatment-target implications for the interferonopathy component of SAMHD1 haploinsufficiency.
DOI: 10.1002/adfm.202525671

Mitophagy in Macrophages: A Metabolic Checkpoint in Inflammation‐to‐Repair Transition in Atherosclerosis (from Cardiology/Atherosclerosis)
Jie Zhou; Hanxiu Liu; Sen Ma; Haoyang Wang; Ni He — Journal of the American Heart Association 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy, treatment-target

This review directly covers the core mechanistic triad (mtDNA release → cGAS-STING activation, NLRP3 inflammasome, and PINK1/Parkin-dependent mitophagy block) that underpins the RED and BLUE streams of the SAMHD1 A565T interferon-mitochondrial syndrome, and discusses therapeutic agents (metformin, resveratrol) that could modulate these pathways in affected macrophages.
DOI: 10.1161/jaha.125.048103

Mitochondria at the Crossroads of Cardiovascular Disease: Mechanistic Drivers and Emerging Therapeutic Strategies (from Cardiology)
Sonila Alia; G. Pedriali; P. Compagnucci; Y. Valeri; Valentina Membrino — Cells 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy, POLG-mtDNA, treatment-target, other

This review directly covers cGAS-STING activation by released mtDNA, NLRP3 inflammasome, PINK1/Parkin mitophagy block, mPTP/VDAC-driven mtDNA escape, and therapeutic targets (MCC950-class, SGLT2i, mitophagy activators) that map precisely onto the RED, BLUE, and PURPLE mechanistic streams of the SAMHD1 interferonopathy model, providing translational therapeutic framing in a cardiovascular context relevant to the family's potential cardiac manifestations.
DOI: 10.3390/cells15040372

RIG‐I Mediated Neuron‐Specific IFN Type 1 Signaling in FUS‐ALS Induces Neurodegeneration and Offers New Biomarker‐Driven Individualized Treatment Options for (FUS‐)ALS (from Neurology/ALS)
Marcel Naumann; Theresa M Wierschin; S. Kretschmer; Banaja P. Dash; Aaron Held — Advanced Science 2026
Score: 7/10 | Pathways: cGAS-STING, JAK-STAT, ISG15-mitophagy, POLG-mtDNA, treatment-target, other

This paper directly demonstrates that mitochondrial dsRNA drives RIG-I→TBK1→IRF3→ISG upregulation in motor neurons, that IFN-I signaling alone causes axonal degeneration, and that ruxolitinib (JAK inhibitor) reverses it—mechanistically paralleling the BLUE and RED streams of the SAMHD1 interferonopathy model (cGAS-STING/IRF3 activation from mitochondrial nucleic acid escape → ISG-driven mitophagy block → neurodegeneration), with ruxolitinib representing a directly actionable treatment target already relevant to the family's condition.
DOI: 10.1002/advs.202417135

🟡 Medium Relevance

Hypoxia-mimicked mitochondrial stress triggers APOBEC3A-mediated DNA damage via non-canonical innate immune activation. (from oncology/cancer biology)
R. Suspène; Béibhinn O’Hora; Constance de Maere d’Aertrycke; Lydie Couturier; T — NAR molecular medicine 2026
Score: 6/10 | Pathways: VDAC1, POLG-mtDNA, cGAS-STING, other

This paper demonstrates that cytosolic mtDNA release (a central mechanism in the BLUE stream via VDAC1 macropore) can activate innate immune signaling via an interferon-independent RIG-I/TRAF6/NF-κB route rather than cGAS-STING, directly linking mitochondrial dysfunction and metabolic reprogramming to genomic instability—relevant because SAMHD1 haploinsufficiency similarly drives cytosolic mtDNA accumulation and innate immune activation, and the APOBEC3A-mediated mutagenesis mechanism adds a novel genomic instability dimension that could contribute to the family's cancer phenotypes (myeloma, endometrial, prostate, duodenal).
DOI: 10.1093/narmme/ugag012

Pathogenic role of mitochondrial DNA mutations in heart failure: clinical features, mechanisms, and therapeutic prospects (from Cardiology)
Mingyang Ni; Aijia Zheng; Hang Zheng; Wenqing Jia; Yuansheng Wang — Frontiers in Cardiovascular Medicine 2026
Score: 6/10 | Pathways: POLG-mtDNA, cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy, clinical-phenotype, other

This review directly covers mtDNA mutation-driven innate immune activation (cGAS-STING, NLRP3), mitochondrial dynamic homeostasis disruption, POLG-related replication errors, and oxidative mtDNA damage in cardiac disease—all of which are mechanistically central to the SAMHD1 A565T interferonopathy-mitochondrial syndrome, and the family phenotype includes mitochondrial cardiomyopathy risk, making this a clinically adjacent bridge paper despite no direct SAMHD1 content.
DOI: 10.3389/fcvm.2026.1781927

No Correlation Between Interferon Signaling and Cytosolic Mitochondrial DNA/RNA Leakage in Cultured Skin Fibroblasts of Patients With Mitochondrial Diseases (from Mitochondrial disease / clinical genetics)
M. Marchais; Alessandra Pennisi; Alexandre Pierga; A. Lepelley; Nicolas Cagnard — European Journal of Immunology 2026
Score: 6/10 | Pathways: cGAS-STING, POLG-mtDNA, JAK-STAT, AGS-spectrum, ME-CFS, other

This paper directly investigates the cytosolic mtDNA leakage → interferon signaling axis in mitochondrial disease patient fibroblasts, finding a surprising lack of correlation that critically informs whether VDAC1/cGAS-STING-mediated mtDNA escape will be detectable in cellular models of SAMHD1 haploinsufficiency, and highlights that 43% penetrance of IFN signatures in mitochondrial disease fibroblasts mirrors incomplete expressivity seen in the SAMHD1 family — directly relevant to both disease modeling strategy and the BLUE stream mechanism.
DOI: 10.1002/eji.70176

Emerging frontiers in the mitochondrial regulation of dendritic cell biology (from Immunology/Redox Biology)
B. Chen; J. U. Mayer; Redox Biology — Redox Biology 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy, JAK-STAT, POLG-mtDNA, mTOR-lysosomal, ME-CFS, other

This review directly addresses mtDNA release (VDAC1/cGAS-STING axis), mitochondrial ROS, NLRP3 activation, and bioenergetic rewiring in dendritic cells — all core pathways of the SAMHD1 interferonopathy mechanism — and explicitly hypothesizes that genetic mitochondrial disorders (matching the SAMHD1 haploinsufficiency profile) disrupt DC biology to produce chronic inflammation, immune dysregulation, and heightened infection susceptibility, making it highly adjacent to the family phenotype even without direct SAMHD1 mention.
DOI: 10.1016/j.redox.2026.104032

Mitochondrial Quality Control in Macrophages during Cardiovascular Disease. (from Cardiology)
R. Falconer; E. Day — The Canadian journal of cardiology 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy, POLG-mtDNA, treatment-target, other

This review directly covers mtDNA release, VDAC1-mediated macrophage inflammatory signaling, mitophagy dysfunction (MFN/fission-fusion dynamics), and cGAS-STING/NLRP3 activation in cardiovascular disease macrophages—all core mechanistic streams of the SAMHD1 A565T interferonopathy model—while also discussing statins, SGLT2 inhibitors, and GLP-1 agonists as MQC-restoring therapies relevant to the family's cardiovascular phenotype risk.
DOI: 10.1016/j.cjca.2026.02.034

STING activation in renal and prostatic inflammation: potential therapeutic targets and immune regulation (from Urology/Nephrology)
Shilong Cao; Zhuolin Kong; Haoyuan Zheng; Peng Xin; Yutao Wang — Frontiers in Immunology 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, JAK-STAT, BIK-cancer, treatment-target, clinical-phenotype

This review directly covers the cGAS-STING pathway (BLUE stream) in renal and prostatic contexts, with mechanistic discussion of mitochondrial injury-driven STING activation, NF-κB signaling, and translational therapeutic strategies including STING inhibitors—all directly relevant to the disease mechanism, plus prostate cancer susceptibility (BIK axis) noted in the family phenotype.
DOI: 10.3389/fimmu.2026.1743707

Mitochondria in T-cell tumor immunity and tumor therapies targeting mitochondria (Review) (from Oncology/Tumor Immunology)
Minjie Zhou; Yijie Xie; Zhipeng Liu; Yi He; Yibing Yin — Oncology Reports 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy, POLG-mtDNA, treatment-target, other

This review directly covers cGAS-STING, TLR9, and NLRP3 activation by released mtDNA, mitochondrial fusion/fission dynamics (relevant to MFN1/MFN2 and ISGylation-driven mitophagy block), and metabolic reprogramming—all core pathways in the SAMHD1 A565T mechanism—but in the context of T-cell tumor immunity rather than interferonopathy or haploinsufficiency, making it an adjacent mechanistic resource with treatment-targeting implications rather than a direct disease model.
DOI: 10.3892/or.2026.9064

Advances in Elucidating the Mitochondrial DNA Mechanisms Underlying Ozone-Induced Inflammation (from environmental toxicology / pulmonology)
Qian Chen; Hao Liu; Junhe Zhou; Yongjie Wei; Lingyan He — Toxics 2026
Score: 5/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, ME-CFS

This review covers mtDNA release from dysfunctional mitochondria as a DAMP activating innate immune pathways (cGAS-STING, NLRP3) — mechanistically overlapping with the BLUE and PURPLE streams of the SAMHD1 syndrome — but the driver is exogenous ozone exposure rather than dNTP pool dysregulation, making the connection indirect and context-dependent.
DOI: 10.3390/toxics14030248

Clotting the Gap Between Mitochondria-Mediated Immunity and Mitochondrial Transfer (from Hematology/Cardiovascular (platelet biology, antiphospholipid syndrome, transfusion medicine))
Florian Tupin; Jorge A. Gonzalez-Chapa; Jay H. Chung; C. Lood; Éric Boilard — Circulation Research 2026
Score: 5/10 | Pathways: cGAS-STING, VDAC1, NLRP3, POLG-mtDNA, ME-CFS, other

This review covers mtDNA release through mitochondrial pores (directly implicating VDAC1 macropore), cytoplasmic mtDNA triggering cGAS-STING innate immune responses, and extracellular mitochondria as DAMPs — all core to the BLUE and PURPLE streams of the SAMHD1 A565T mechanism — but focuses primarily on platelet-derived extracellular mitochondria and mitochondrial transplantation rather than on the dNTPase/SAMHD1 axis, making the connection indirect but mechanistically meaningful.
DOI: 10.1161/circresaha.125.326987

Abstract 3789: Treatment with ACR-2316, a potential first- and best-in-class WEE1/PKMYT1 inhibitor, combined with anti-PD-L1 induces complete tumor regression with durable immune memory (from Oncology)
Taronish D. Dubash; J. Baddour-Sousounis; A. Elbakry; Jessica Hopkins; Subodh Ku — Cancer Research 2026
Score: 5/10 | Pathways: cGAS-STING, POLG-mtDNA, VDAC1, BIK-cancer, treatment-target

ACR-2316 induces mitochondrial DNA fragmentation activating cGAS and type I interferon signaling—mechanistically parallel to the SAMHD1 haploinsufficiency disease model's BLUE stream (VDAC1/mtDNA escape→cGAS→IFN-I), but the clinical context is oncology tumor killing rather than constitutive interferonopathy, making it indirectly relevant as a mechanistic analog and potential treatment-context comparator.
DOI: 10.1158/1538-7445.am2026-3789

🟢 Low Relevance

Macrophage extracellular traps in autoimmunity: In vivo definition, pathogenic circuits, and therapeutic targeting. (from Rheumatology/innate immunology)
Mengchao Liu; Mingzhe Wang; Haoran Dai; H. Jiang; Wenbin Liu — Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2026
Score: 4/10 | Pathways: cGAS-STING, NLRP3, other

METs externalize mitochondrial DNA and activate nucleic-acid-sensing pathways (cGAS-STING, NLRP3) relevant to the interferonopathy mechanism, but the paper focuses on extracellular trap biology in classical autoimmune diseases rather than SAMHD1 haploinsufficiency, mitochondrial dNTP pool dysregulation, or any core pathway node specific to the A565T disease model.
DOI: 10.1016/j.biopha.2026.119180

Stimulator of interferon genes (STING)‐activating nanomedicines: Translating innate immune modulation into effective therapy for triple‐negative breast cancer (from Oncology/nanomedicine)
Harshita Singhai; T. Alqahtani; Humood Al Shmrany; Garima Gupta; U. Patil — Clinical and Translational Medicine 2026
Score: 3/10 | Pathways: cGAS-STING, JAK-STAT, POLG-mtDNA, treatment-target

While this paper covers STING pathway activation and type I interferon signaling (core to the disease mechanism), its focus is entirely on therapeutic STING agonism via nanoparticles for TNBC — the opposite direction of relevance (activation vs. pathological overactivation) — and contains no mechanistic insights directly applicable to SAMHD1 haploinsufficiency, chronic interferonopathy, or the family phenotype.
DOI: 10.1002/ctm2.70580

Abstract 062 | Mitochondrial signaling in age-related conditions (from Gerontology/translational myology)
A. Picca — European Journal of Translational Myology 2026
Score: 3/10 | Pathways: POLG-mtDNA, cGAS-STING, NLRP3, other

This highly general review discusses mitochondrial signaling in aging—including mtDNA escape, innate immune activation, and inflammatory amplification—which tangentially overlaps with PURPLE/BLUE stream mechanisms, but contains no specific engagement with SAMHD1, cGAS-STING, NLRP3, VDAC1, ISG15, or any pathway directly operative in the disease model.
DOI: 10.4081/ejtm.2026.15061

Mitochondria as Master Regulators: Linking Energy, Immunity, and Inflammation (from Osteopathic/Family Medicine)
Steve Kamajian — Journal of the Osteopathic Family Physicians of California 2026
Score: 3/10 | Pathways: NLRP3, POLG-mtDNA, ME-CFS, other

This review broadly covers mitochondrial dysfunction, mtDNA release, inflammasome activation, and fatigue/post-exertional symptom clusters in a primary care context, touching on mechanisms relevant to the disease model but without any specificity to SAMHD1, cGAS-STING, VDAC1, ISG15, or the interferon-mitochondrial axis.
DOI: 10.58858/050102

↩ Re-run 07:21 UTC | Model: claude-sonnet-4-6

Summary: 0 new papers | 0 high-relevance (≥7) | 0 medium (5–6) | 0 low (3–4)

No new papers above threshold in this run.

April 1, 2026
in Monthly Synthesis, treatment-target, cGAS-STING, VDAC1, NLRP3
18 min read

SAMHD1 Research Digest — 2026-04-22

Generated by samhd1_monitor | Model: claude-haiku-4-5-20251001

Summary: 41 papers evaluated | 28 high-relevance (≥7) | 12 medium (5–6) | 1 low (3–4) | 0 scored <3

🔴 High Relevance (Score 7–10)

Added to Zotero automatically

cGAS inhibitor IMSB301 modifies interferon signalling in peripheral mononuclear cells of SAMHD1 genetic interferonopathy in vitro (from Clinical immunology / translational therapeutics (immunological phenotyping of rare genetic disease))
V. Han; J. Hayes; Lijun Sun; Teresa Mooneyham; Michelle Lorentzos — Clinical & Translational Immunology 2026
Score: 9/10 | Pathways: cGAS-STING, ISG15-mitophagy, JAK-STAT, AGS-spectrum, treatment-target

Direct demonstration of cGAS inhibitor IMSB301 reducing interferon signaling in SAMHD1-mutant PBMCs with quantified ISG15 downregulation; critical proof-of-concept for BLUE loop (VDAC1-mtDNA-cGAS-STING-IRF3-IFN-I) therapeutic intervention in genetic interferonopathy.
DOI: 10.1002/cti2.70090

Mitochondrial Dysfunction and Immunoinflammatory Remodeling in Heart Failure: Emerging Role of the mtDNA-cGAS/STING Axis and Therapeutic Opportunities. (from Cardiology: addresses cardiac manifestations of mtDNA-driven immunoinflammation and VDAC1-mediated mtDNA escape as mechanisms of cardiomyocyte loss and fibrosis, extending SAMHD1 pathophysiology beyond CNS/systemic manifestations to cardiac vulnerability in interferon-driven disease.)
Zhang Xi; Xia Xiangchen; Zhang Yanmin; Liu Xiaomin; Wei Xiaoyu — 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, ISG15-mitophagy, POLG-mtDNA, treatment-target, clinical-phenotype

Direct mechanistic focus on mtDNA-cGAS/STING axis triggering sterile inflammation via mitochondrial dysfunction, impaired mitophagy, and mitochondrial dynamics—core BLUE and RED loop pathways in SAMHD1 haploinsufficiency—with actionable therapeutic targets (cGAS/STING inhibitors, mitophagy enhancers) applicable to convergent interferon-mitochondrial syndrome.
DOI: 10.1016/j.phrs.2026.108195

Targeting VDAC1 to protect against mitochondria-linked cell death pathways: apoptosis, pyroptosis, ferroptosis, and associated diseases. (from Cell death biology / mitochondrial pathobiology; translational to neurology (Alzheimer's) and gastroenterology (IBD) but mechanism-agnostic to tissue origin)
Shteinfer-Kuzmine A; Nivedita A Karunanithi; Santhanam M; Trishna S; Swerdlow R * — 2026
Score: 8/10* | Pathways: VDAC1, NLRP3, cGAS-STING, treatment-target, clinical-phenotype

Core VDAC1-NLRP3 axis directly addressed with therapeutic VBIT-4 inhibitor; validates Loop A (SAMHD1/VDAC1 → mtDNA escape → cGAS-STING) and Loop B (NLRP3 inflammasome inhibition); demonstrates preclinical proof-of-concept for pyroptosis-ferroptosis blocking in inflammatory disease models mechanistically aligned with A565T haploinsufficiency convergent interferon-mitochondrial syndrome.
DOI: 10.1007/s10495-025-02217-7

Targeting VDAC1-dependent mtDNA release attenuates fibroblast innate immune activation and vitiligo pathogenesis. (from Dermatology/cutaneous immunology)
Jinpeng Lv; Huansha Zhang; Wenhao Yu; Peiwen Jiang; Chuanwei Yin — International immunopharmacology 2026
Score: 8/10 | Pathways: VDAC1, cGAS-STING, NLRP3, poliosis-neural-crest, treatment-target

Directly demonstrates VDAC1-dependent mtDNA release → cGAS-STING + NLRP3 activation in dermal fibroblasts under oxidative stress, with VBIT-4 therapeutic validation in vivo; mechanistically core to BLUE and PURPLE loops in A565T haploinsufficiency, and poliosis (melanocyte destruction) is a documented family phenotype linked to neural crest interferonopathy.
DOI: 10.1016/j.intimp.2026.116411

PGAM1-dependent VDAC1 oligomerization disrupts mitochondrial quality control to drive doxorubicin cardiotoxicity via the cGAS-STING-ferroptosis axis. (from Cardiology/Oncology (doxorubicin cardiotoxicity model); bridges to A565T family cardiology phenotypes and chemotherapy-induced interferonopathy risk)
Yukun Li; Sicheng Zheng; Haowen Zhuang; Ji Wu; Junyan Wang — Free radical biology & medicine 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, ISG15-mitophagy, treatment-target

Direct mechanistic demonstration of VDAC1 oligomerization → mtDNA leak → cGAS-STING activation → ferroptosis in cardiotoxicity; core to BLUE loop and SAMHD1 A565T pathophysiology; identifies druggable VDAC1/STING nodes and reveals ferroptosis as downstream effector of mitochondrial quality control collapse.
DOI: 10.1016/j.freeradbiomed.2026.01.065

Mitochondrial DNA release via VDAC1 in keratinocytes: a key driver of innate immunity and vitiligo pathogenesis (from Dermatology/Pigmentation Biology)
Jinpeng Lv; Wenhui Xu; Peiwen Jiang; Wenhao Yu; Hui Xue — Cell Death & Disease 2026
Score: 8/10 | Pathways: VDAC1, cGAS-STING, NLRP3, poliosis-neural-crest, treatment-target

Demonstrates VDAC1-dependent mtDNA release → cGAS-STING + NLRP3 activation in keratinocytes with oxidative stress trigger and VBIT-4 therapeutic intervention; directly maps Blue and Purple loops in A565T pathogenesis and explains melanocyte dysfunction (poliosis phenotype) through same dual-pathway innate immune mechanism.
DOI: 10.1038/s41419-026-08585-5

Mitochondrial DNA: A Key Alarmin Igniting the Inflammasome Fire in Health and Disease. (from Innate immunology/inflammasome biology)
W. Park — Immunology 2026
Score: 8/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, ISG15-mitophagy, treatment-target

This review directly synthesizes the mtDNA-inflammasome axis (PURPLE and BLUE loops) central to SAMHD1 A565T pathogenesis, covering VDAC1-mediated mtDNA escape, cGAS-STING activation, NLRP3 inflammasome triggering by ox-mtDNA, and mPTP opening—all molecular anchors of the convergent interferon-mitochondrial syndrome; therapeutic modulation of this axis is directly actionable for the family phenotype.
DOI: 10.1111/imm.70111

Spleen Tyrosine Kinase (SYK) is Necessary for cGAS-STING Signaling in Müller Glia and Visual Function Deficits in Diabetic Mice. (from Ophthalmology/Neuroimmunology—retinal glial inflammation model; mechanistically relevant to CNS manifestations in convergent interferon-mitochondrial syndrome but requires translation from diabetes-induced to SAMHD1-haploinsufficiency context.)
Yerlikaya Esma I; Sunilkumar Siddharth; Subrahmanian Sandeep M; Toro Allyson L; * — 2026
Score: 7/10* | Pathways: cGAS-STING, NLRP3, VDAC1, JAK-STAT, treatment-target

Paper demonstrates SYK as essential upstream regulator of cGAS-STING pathway activation downstream of mitochondrial DNA escape in glial cells; SYK inhibition blocks inflammatory cascade (IL-1β, CCL2), offering potential treatment strategy for interferonopathy-driven tissue dysfunction analogous to SAMHD1 haploinsufficiency mechanisms.
DOI: 10.1002/glia.70155

Micropterus salmoides rhabdovirus G protein interacts with VDAC to trigger mitochondrial DNA/cGAS-STING pathway-mediated antiviral immune responses. (from Virology/Ichthyology)
Zhu Qiang; Gu Xie; Zhao Lu-Chuan; Zhang Ze-Sheng; Huang Meng-Meng — 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, treatment-target

Fish rhabdovirus study demonstrates VDAC1/2-mediated mtDNA escape triggering cGAS-STING activation—a core BLUE-loop mechanism central to SAMHD1 A565T pathophysiology—with NSC15364 VDAC inhibition as proof-of-concept for pathway suppression applicable to human interferonopathy.
DOI: 10.1016/j.fsi.2026.111353

Mitochondrial 8-Oxoguanine DNA Glycosylase 1-Mitochondrial Permeability Transition Pore Axis Drives Mitochondrial DNA Escape and Accelerates Osteoarthritis Progression. (from Rheumatology/Orthopedics (osteoarthritis pathogenesis); paper does not address SAMHD1 but mechanism is core to family's multi-system interferonopathy and suggests rationale for OA clustering in SAMHD1 mutation carriers.)
Huang Shiqian; Yu Heting; Qi Weizhong; Lin Na; Chen Jianmao — 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, treatment-target, clinical-phenotype

Paper directly demonstrates the mtDNA escape → cGAS-STING → NF-κB axis (Loop A/Blue pathway) via VDAC1-mediated permeability transition and OGG1-driven oxidized mtDNA accumulation, with dual therapeutic intervention (OGG1 activation + VDAC1 inhibition via cyclosporin A) showing synergistic suppression of this cascade in an inflammatory disease model, providing direct mechanistic and therapeutic validation highly relevant to SAMHD1 A565T haploinsufficiency-driven interferonopathy.
DOI: 10.34133/research.1235

Microglial NEDD4L activates mtDNA-cGAS-STING pathway and promotes neuroinflammation after intracerebral hemorrhage through impairing mitophagy (from Neurology/neuroimmunology; intracerebral hemorrhage context differs from rare disease genetics but establishes NEDD4L-STAT2-cGAS-STING-Parkin-mitophagy axis as generalizable mechanism applicable to A565T neuroinflammatory phenotypes (AuDHD, ME/CFS post-viral trigger, potential CNS involvement).)
Wang Jin; Ma Yuyuan; Yang Kaichuang; Zhang Weihua; Wang Weiyu — 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, ISG15-mitophagy, JAK-STAT, treatment-target

NEDD4L-mediated Parkin ubiquitination impairing mitophagy and triggering mtDNA-cGAS-STING activation represents a novel mechanistic node upstream of the convergent interferon-mitochondrial syndrome; directly relevant to RED and BLUE loop pathology in A565T haploinsufficiency, with potential JAK-STAT2 intersection and STAT2-dependent therapeutic target implication for neuroinflammatory manifestations.
DOI: 10.21203/rs.3.rs-9225741/v1

ADT-OH promotes mitophagy and suppresses the cytosolic mtDNA-cGAS-STING inflammatory cascade in microglia. (from Neurology/Parkinson's disease research—provides proof-of-concept for microglial-centric cGAS-STING suppression and mitophagy enhancement as therapeutic strategy applicable to SAMHD1-driven neuroinflammation and post-viral neurological sequelae.)
Hou Xiao-Ou; Wang Miao; Deng Rong; Lu Yi-Fan; Zhang Jin-Ru — 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, ISG15-mitophagy, POLG-mtDNA, treatment-target

ADT-OH directly targets the cytosolic mtDNA-cGAS-STING inflammatory cascade and PINK1-PARKIN mitophagy, two core pathways in SAMHD1 haploinsufficiency pathophysiology; demonstrates a novel pharmacologic approach to suppress both mtDNA escape (BLUE loop) and restore mitophagic flux (RED loop blockade reversal) in a neuroinflammatory context relevant to ME/CFS and AuDHD neurobiology.
DOI: 10.1038/s41401-026-01789-7

Irradiated Liver Cancer Cell Vaccine Transfected With GM-CSF Induces Specific and Long-Lasting Anti-tumour Immunity Through the Synergistic Effect of Oxidised mtDNA and GM-CSF. (from Oncology/Cancer Immunotherapy)
Song Zhiruo; Jiang Yujie; Zhang Yu; Ao Danyi; Ye Chunjun — 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, treatment-target

Paper demonstrates ox-mtDNA-driven cGAS-STING activation as immunostimulatory mechanism in cancer context; directly relevant to understanding how oxidized mtDNA (a cardinal feature of SAMHD1 A565T haploinsufficiency via POLG stalling and VDAC1 macropore) could be therapeutically harnessed, and inversely suggests that pathologic ox-mtDNA accumulation in this family drives aberrant interferonopathy.
DOI: 10.1111/cpr.70198

Clotting the Gap Between Mitochondria-Mediated Immunity and Mitochondrial Transfer. (from Hemostasis/Transfusion Medicine and Platelet Biology—bridging to immunology and mitochondrial pathology)
Tupin Florian; Gonzalez-Chapa Jorge A; Chung Jay H; Lood Christian; Boilard Eric — 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, NLRP3, ISG15-mitophagy, treatment-target, clinical-phenotype

Paper establishes platelet-derived extracellular mitochondria as primary source of cytoplasmic mtDNA triggering cGAS-STING and innate immunity, directly supporting the BLUE loop (VDAC1 macropore → mtDNA escape → cGAS activation) central to SAMHD1 A565T pathogenesis; additionally addresses antimitochondrial antibodies and immune-mitochondrial cross-talk relevant to interferonopathy manifestations, and mitochondrial transplantation as potential therapeutic avenue for defective mitochondrial states.
DOI: 10.1161/circresaha.125.326987

Targeting Mitochondrial Permeability and Cytosolic mtDNA Release: Astragaloside IV Suppresses cGAS-STING Signaling Pathway to Protect against Cadmium-induced Hepatotoxicity. (from Toxicology/Pharmacology)
Hao Xu; Jingyi Yang; Yu Zhang; Shihui Li; Ziwei Wang — Free radical biology & medicine 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, treatment-target

Paper directly demonstrates mitochondrial permeability control → cytosolic mtDNA release → cGAS-STING suppression via natural compound; mechanism maps to BLUE loop (VDAC1 macropore closure) and offers pharmacological probe for SAMHD1 haploinsufficiency interferonopathy, particularly relevant for hepatotoxicity clustering in family phenotype.
DOI: 10.1016/j.freeradbiomed.2026.01.027

Zinc protects against neuroinflammation after spinal cord injury by regulating mitophagy-dependent mtDNA-cGAS-STING signaling. (from Neurology/Neurosurgery (spinal cord injury model))
Feng Jin; Zengtao Song; Yu Deng; Hongkai Yang; Yajiang Yuan — Free radical biology & medicine 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, ISG15-mitophagy, POLG-mtDNA, treatment-target

Paper demonstrates zinc-mediated suppression of mtDNA-cGAS-STING signaling through enhanced PINK1-Parkin mitophagy and VDAC1 stabilization—directly targeting two core pathological loops (A: VDAC1 macropore/cGAS; red: ISG15-mitophagy block) operative in SAMHD1 A565T haploinsufficiency, with potential therapeutic relevance for the convergent interferon-mitochondrial syndrome phenotype.
DOI: 10.1016/j.freeradbiomed.2026.02.010

Fumarate loss destabilizes mitochondria and activates cGAS-STING in OLP. (from Metabolic biochemistry / TCA cycle dysregulation)
Yan Hu; Huyan Chen; Chenyun Ding; Sheng Zhang; Qing Chen — Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, treatment-target, other

Paper demonstrates metabolically driven mtDNA destabilization → cytosolic mtDNA leakage → cGAS-STING activation (BLUE loop) with therapeutic intervention (fumarate supplementation) that directly parallels the mitochondrial-interferon axis in SAMHD1 haploinsufficiency, though without addressing the upstream dNTP or SAMHD1 component.
DOI: 10.1016/j.biopha.2026.119127

DNMT1 knockdown mitigates sepsis-induced myocardial dysfunction by preventing TFAM-mediated mitochondrial DNA cytosolic escape and subsequent cGAS-STING to regulate macrophage M2 polarization. (from Cardiology/Critical Care (sepsis model) bridging to immunometabolism and mitochondrial innate immunity.)
Min Li; Yang Liu; Kuo Qu; Yu Zhang; Hailing Yang — Biochemical pharmacology 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, treatment-target

Paper demonstrates DNMT1→TFAM→mtDNA cytosolic escape→cGAS-STING axis in sepsis-induced cardiomyopathy with therapeutic validation; directly relevant to BLUE loop (VDAC1-mediated mtDNA release triggering cGAS-STING-IRF3) and offers epigenetic intervention strategy (DNMT1 inhibition) applicable to SAMHD1 A565T convergent interferonopathy, though lacks direct SAMHD1 or dNTPase connection.
DOI: 10.1016/j.bcp.2026.117709

Neuronal TLR4 upregulation activates the cGAS-STING pathway to induce ferroptosis in EAE mice. (from Neurology/Neuroimmunology; ferroptosis as iron-dependent cell death mechanism bridges SAMHD1-mitochondrial axis with neuronal pathology in MS/EAE, contextually relevant to AuDHD/neurofunctional impairment in proband.)
H. Qin; Lingfei Yang; Jing Du; XiaoMeng Xu; Ziyi Chen — International immunopharmacology 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, treatment-target

Paper demonstrates TLR4-mtDNA-cGAS-STING axis driving ferroptosis in neuroinflammation; directly relevant to SAMHD1 A565T's BLUE pathway (mtDNA escape → cGAS-STING → IFN-I) and offers mechanistic validation plus ferroptosis as a potential neurotoxic endpoint in interferon-driven neuronal injury; therapeutic blocking of ferroptosis (Liproxstatin-1) suggests treatment avenue applicable to A565T-driven neurodegeneration.
DOI: 10.1016/j.intimp.2026.116364

Selective antagonism of adenosine A2A receptor reduces hypobaric hypoxia-induced neuroinflammation by inhibiting cGAS-STING pathway (from Neurology/hypoxia physiology; adenosine signaling as upstream regulator of mitochondrial permeability transition via cAMP-EPAC1 axis not previously foregrounded in SAMHD1 haploinsufficiency mechanistics.)
Hongbo Cheng; Yehui Gao; Huiying Shang; Weiye Han; Xiaotong Zhang — Scientific Reports 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, treatment-target

ADORA2A antagonism reduces cGAS-STING activation via VDAC1-mediated mtDNA release inhibition, demonstrating a druggable upstream control point for the core BLUE pathway; translatable as potential JAK-sparing interferonopathy modifier for ME/CFS-SAMHD1 cohorts.
DOI: 10.1038/s41598-025-30717-8

Mitochondrial transfer from immune to tumor cells enables lymph node metastasis. (from Oncology/Tumor Immunology)
Azusa Terasaki; Keshav Bhatnagar; Alexis T. Weiner; Yuhao Tan; Viktoria Szeifert — Cell metabolism 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, ISG15-mitophagy, treatment-target

Paper demonstrates cGAS/STING-driven type I interferon activation triggered by mtDNA cytosolic leak from VDAC1-like mitochondrial dysfunction in tumor-immune crosstalk, directly paralleling Loop A and Loop B mechanisms in SAMHD1 A565T haploinsufficiency; reveals immunosuppression and metastatic niche formation as downstream IFN-I consequence, relevant to understanding how convergent interferon-mitochondrial syndrome enables immune evasion and cancer progression in affected families.
DOI: 10.1016/j.cmet.2025.12.014

Macrophage TRIM21 Inhibition Ameliorates Murine Acute Pancreatitis via PHB2‐Mediated Mitochondrial Stabilization (from Gastroenterology/Pancreatology)
Yansong Xu; Yuansong Sun; Xin Zhou; Kai Song; Chunlin Yin — Advanced Science 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, ISG15-mitophagy, NLRP3, treatment-target

TRIM21-PHB2-K11-ubiquitin axis directly impairs mitophagy and triggers mtDNA cytosolic accumulation → cGAS-STING activation; parallels the RED and BLUE pathways in SAMHD1 A565T disease with novel upstream ubiquitin control point, and quisinostat offers mechanistically relevant therapeutic angle for interferonopathy-driven inflammation.
DOI: 10.1002/advs.202517877

Abstract 5598: Exploiting electron transport chain dynamics to sensitize OXPHOS-dependent cancers to immunotherapy (from Oncology/metabolic immunology; bridges to rare disease via mechanistic insight into how ETC perturbation and mtDNA integrity control innate immunity—directly applicable to understanding cancer susceptibility clustering (prostate, multiple myeloma, endometrial) in A565T families and potential JAK/STING-targeted interventions.)
Haojie Dong; Guoyun Kao; Umesh Yadav; Lei Zhang; Arshad J. Ansari — Cancer Research 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, VDAC1, treatment-target

Paper demonstrates mechanistic control of cGAS-STING activation through ETC-mtDNA leakage pathway (core Loop A mechanism) and identifies DHODH as a selective tumor-intrinsic regulator; highly relevant to understanding selective cGAS activation in OXPHOS-dependent malignancies that may arise in A565T carriers, and reveals potential therapeutic vulnerability in the cGAS-mtDNA-STING axis central to this interferonopathy.
DOI: 10.1158/1538-7445.am2026-5598

Abstract 3273: The mitochondrial protease YME1L regulates type 1 interferon signaling via the STING pathway in AML (from Oncology/hematology (AML biology), with mitochondrial proteostasis as novel upstream control of interferon pathology distinct from classical dNTPase-centric models.)
Yihe Zhang; G. Thomas; R. Hurren; Yongran Yan; M. Gronda — Cancer Research 2026
Score: 7/10 | Pathways: cGAS-STING, ISG15-mitophagy, VDAC1, treatment-target

YME1L depletion activates cGAS-STING → type I interferon → ISG15 upregulation via mitochondrial dsDNA accumulation; mechanistically parallel to SAMHD1 haploinsufficiency-driven interferonopathy, with STING pharmacological inhibition as validated therapeutic checkpoint relevant to JAK inhibitor strategy in SAMHD1-driven disease.
DOI: 10.1158/1538-7445.am2026-3273

TRIM25 triggers pyroptosis through mitochondrial DNA release in intestinal ischemia-reperfusion injury. (from Surgery/Gastroenterology (intestinal ischemia-reperfusion injury model); mechanistic findings transferable to post-infectious/hypoxic triggers of mitochondrial dysfunction in ME/CFS and interferonopathy.)
Song Yao; Xiaolong Lu; Ximeng Ren; Meng Li; Fanrui Meng — Free radical biology & medicine 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, treatment-target

Paper demonstrates a novel TRIM25→PGAM5→mitochondrial permeability→mtDNA release→cGAS-STING→NLRP3 axis in intestinal I/R, directly paralleling the core BLUE (VDAC1/mtDNA escape) and PURPLE (NLRP3) pathways implicated in SAMHD1 A565T pathophysiology, with potential therapeutic implications via PGAM5/TRIM25 inhibition as complement to cGAS/STING blockade.
DOI: 10.1016/j.freeradbiomed.2026.02.019

Efficacy of JAK1/2 inhibitors in AGS genes-related interferonopathies: A multicenter retrospective observational study with treated vs untreated comparison. (from Pediatric Genetics / Metabolic Medicine)
G. Marinella; Ylenia Vaia; Davide Politano; J. Galli; F. Nicita — Molecular genetics and metabolism 2026
Score: 7/10 | Pathways: JAK-STAT, AGS-spectrum, treatment-target, clinical-phenotype

Direct evidence that JAK1/2 inhibitors (baricitinib, ruxolitinib) show efficacy in AGS-related interferonopathies with heterogeneous neurological response; highly relevant as these agents target the downstream JAK-STAT effector arm of the proband's cGAS-STING-IRF3 pathway and establish therapeutic precedent for SAMHD1 haploinsufficiency interferonopathy, though mechanistic data on non-JAK pathways (NLRP3, VDAC1, ISG15-mitophagy block) limit perfect alignment.
DOI: 10.1016/j.ymgme.2026.109907

Beyond the interferon score: neurofilament light chain and glial fibrillary acidic protein capture immune-mediated neuroinjury and response to JAK inhibition in Aicardi–Goutières syndrome (from Neurology/Neuroimmunology—bridges quantitative neuroaxonal injury assessment (pNfL/pGFAP) to immunotherapy response monitoring in interferonopathies, critical for rare SAMHD1 cohorts where CNS involvement requires objective disease tracking.)
Lisa Wege; Christian Klemann; Sandy Siegert; Annette E Bley; S. Koss — Frontiers in Immunology 2026
Score: 7/10 | Pathways: JAK-STAT, cGAS-STING, AGS-spectrum, treatment-target, clinical-phenotype

AGS is the prototypical type I interferonopathy on the genetic spectrum with SAMHD1 mutations; this paper establishes pNfL/pGFAP as biomarkers capturing immune-mediated neuroinjury and JAK inhibitor response superior to interferon score alone, directly applicable to monitoring SAMHD1 p.A565T haploinsufficiency-driven convergent interferonopathy with documented neurological involvement (AuDHD) in the proband.
DOI: 10.3389/fimmu.2026.1782352

One mutation, divergent journeys: expanding the clinical spectrum of homozygous SAMHD1 deficiency in childhood (from Rheumatology/Pediatric Rheumatology—recognizes SAMHD1 deficiency as drivers of systemic inflammatory and connective tissue phenotypes rather than isolated neurogenetic disease.)
Hulya Ercan Emreol; Dilara Ünal; D. Ayvaz; Y. Bilginer; S. Özen — Rheumatology (Oxford, England) 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, JAK-STAT, ISG15-mitophagy, AGS-spectrum, treatment-target, clinical-phenotype

Homozygous SAMHD1 missense variant demonstrates JAK-STAT-driven interferonopathy with phenotypic heterogeneity across myopathy/CNS/connective tissue presentations; direct JAK inhibitor efficacy confirms shared dNTPase-dependent interferon pathway, highly relevant to understanding heterozygous A565T haploinsufficiency mechanisms and treatment stratification.
DOI: 10.1093/rheumatology/keaf695

🟡 Medium Relevance (Score 5–6)

Review and add to Zotero manually if warranted

Immune signaling and function in neurodegeneration. (from Neurology/Neuroimmunology)
Latour Yvonne L; McGavern Dorian B — 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, JAK-STAT, ISG15-mitophagy, AGS-spectrum, clinical-phenotype

Review addresses microglia-driven innate immune activation, pattern recognition signaling, and T cell-mediated neuroinflammation in neurodegeneration, directly relevant to understanding how dysregulated cGAS-STING and NLRP3 cascades (triggered by SAMHD1 haploinsufficiency) drive CNS pathology in the proband's AuDHD/ME-CFS convergent phenotype and family neurological clustering.
DOI: 10.1172/jci199850

Puerarin alleviates crystalline silica-induced pulmonary fibrosis by suppressing mtDNA leakage-induced senescence and EMT in alveolar type II cells. (from Occupational/environmental pulmonology and natural product pharmacology)
Gong Shuwen; Su Wei; Wei Xiaoxi; Ma Xinyu; Cao Anqi — 2026
Score: 6/10 | Pathways: cGAS-STING, mtDNA leakage-VDAC1, senescence-EMT, treatment-target

Paper demonstrates mtDNA leakage → cGAS-STING activation in silica-induced lung injury with therapeutic suppression via puerarin, directly paralleling BLUE loop pathology in SAMHD1 haploinsufficiency; occupational lung fibrosis phenotype not family-documented but mechanism overlaps mitochondrial-interferon axis central to disease.
DOI: 10.1016/j.ecoenv.2026.120127

Mitochondria-Derived Vesicles and Mitochondrial Extracellular Vesicles in Health and Cardiovascular Disease. (from Cardiology/mitochondrial biology)
Rapushi Erjola; Aryal Anubhav; Yang Tianyuan; Li Zhixin; Wang Xiaohong — 2026
Score: 6/10 | Pathways: VDAC1, NLRP3, ISG15-mitophagy, POLG-mtDNA, mTOR-lysosomal, clinical-phenotype

MDVs and mitoEVs represent selective quality-control mechanisms for removing oxidized/damaged mitochondrial cargo and mediating organellar crosstalk; directly relevant to SAMHD1 A565T pathogenesis via VDAC1-mediated mtDNA escape, ISG15-blocked mitophagy, and NLRP3 activation from oxidized mtDNA, with potential cardiology phenotype intersection in this multi-generational family.
DOI: 10.1161/circresaha.125.327357

Rethinking Mitochondria: The Extracellular Dimension. (from Cardiovascular pathophysiology and cell biology; bridges to cardiology/mitochondrial cardiomyopathy phenotypes in the family cohort)
Pena-Couso Laura; Makuch Magdalena; Nicolas-Avila Jose Angel — 2026
Score: 6/10 | Pathways: VDAC1, cGAS-STING, NLRP3, ISG15-mitophagy, POLG-mtDNA, clinical-phenotype

Extracellular mitochondria release mechanisms directly engage VDAC1-mediated outer membrane permeability, mtDNA escape (cGAS-STING trigger), and damaged mitochondrial trafficking—core pathways in SAMHD1 A565T pathophysiology—with particular relevance to inflammatory signaling and cardiovascular phenotypes observed in the family.
DOI: 10.1161/circresaha.125.326988

Nanomedicine leverages cuproptosis-mediated cGAS-STING activation to enhance antitumor immunity (from Nanomedicine/oncology—bridges into immunology and mitochondrial biology relevant to SAMHD1-driven innate immunity dysregulation.)
Chunfei Li; Yunze Li; Zhiji Wang; Yumin Wang; Wenzheng Guan — Journal of Nanobiotechnology 2026
Score: 6/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, treatment-target

Paper describes engineered induction of cuproptosis → mitochondrial damage → mtDNA release → cGAS-STING activation, which mirrors the BLUE loop (VDAC1 macropore → cytosolic mtDNA fragments → cGAS-STING) operative in SAMHD1 A565T haploinsufficiency; nanomedicine approach to deliberately trigger this pathway in cancer offers oblique therapeutic insight for blocking pathological cGAS-STING hyperactivation in the disease, but lacks SAMHD1 mechanism and addresses tumor immunity rather than interferonopathy suppression.
DOI: 10.1186/s12951-026-04203-w

Discovering patterns in the pathologic significance of non-missense deleterious variants in RELA. (from Immunology/Rheumatology - NF-κB signaling architecture and therapeutic stratification by variant class (haploinsufficiency vs dominant-negative) provides mechanistic framework for understanding how SAMHD1 haploinsufficiency-driven cGAS-STING/NLRP3 activation propagates through RELA to produce clinical phenotype.)
H. Hayakawa; M. Tsumura; Takanori Utsumi; H. Nihira; Wei-Te Lei — The Journal of allergy and clinical immunology 2026
Score: 6/10 | Pathways: JAK-STAT, IRF7-metabolic, clinical-phenotype, treatment-target

RELA is a critical NF-κB/RelA transcription factor downstream of both cGAS-STING and NLRP3 inflammasome pathways; RELA haploinsufficiency and dominant-negative variants produce type I interferonopathy phenotypes directly relevant to the A565T convergent interferon-mitochondrial syndrome, with treatment implications (anti-TNF vs JAK inhibitors) applicable to managing downstream interferon amplification in this family.
DOI: 10.1016/j.jaci.2026.01.020

Towards effective targeted therapies in morphea. (from Dermatology)
Amanda M Saracino; L. Iyengar; M. Nikpour — Italian journal of dermatology and venereology 2026
Score: 6/10 | Pathways: JAK-STAT, cGAS-STING, ISG15-mitophagy, treatment-target, clinical-phenotype, AGS-spectrum

Morphea is identified as a type I interferonopathy with enriched interferon pathways, Th1/Th17 cytokines, and keratinocyte-derived signaling—mechanistically convergent with SAMHD1 A565T's IRF3-driven IFN-I loop and ISGylation-mediated mitophagy blockade; JAK inhibitors, abatacept, and tocilizumab show clinical efficacy, directly applicable to the proband's interferonopathy management, though no direct SAMHD1 involvement is demonstrated.
DOI: 10.23736/S2784-8671.25.08413-0

Targeting cytokine pathways: the role of biologics in autoinflammatory disorders (from Clinical Immunology/Rheumatology)
T. Koga — Expert Review of Clinical Immunology 2026
Score: 6/10 | Pathways: NLRP3, JAK-STAT, IRF7-metabolic, treatment-target, clinical-phenotype

Review covers IL-1/NLRP3 inflammasome blockade and JAK inhibitors as therapeutic strategies in autoinflammatory/interferonopathic disorders, directly applicable to the convergent interferon–mitochondrial syndrome mechanism in SAMHD1 A565T haploinsufficiency; however, lacks specific SAMHD1 molecular detail or mitochondrial dysfunction pathways (VDAC1, POLG, ISG15-mitophagy), limiting precision for this rare disease.
DOI: 10.1080/1744666X.2026.2625277

Programmable DNAzyme nanocatalysts orchestrate redox-immune coupling for time-gated cancer immunomodulation. (from Nanobiotechnology/cancer immunotherapy; bridges to oncology phenotypes (prostate cancer, multiple myeloma clustering in family) but does not address SAMHD1-dependent tumor suppression or germline haploinsufficiency.)
Wang Lu; Luo Rongping; Zou Lingxiu; Liu Xiaojing; Tang Zhuojia — 2026
Score: 5/10 | Pathways: cGAS-STING, VDAC1, NLRP3, treatment-target

Paper demonstrates mtDNA-triggered cGAS-STING and type I interferon activation via engineered redox-mitochondrial coupling in cancer context; relevant to understanding interferon-mitochondrial syndrome mechanism but lacks SAMHD1 involvement, dNTPase dysregulation, or haploinsufficiency-specific pathophysiology that drives the A565T family phenotype.
DOI: 10.1186/s12951-026-04397-z

Multi-Ion Channel Nanomedicines Targeting Zinc Transporter 1/ATPase Copper Transporters Disrupt Copper/Iron Homeostasis to Enhance Tumor Immunotherapy. (from Nanomedicine/Oncology)
Ma Guangyu; Li Yuting; Li Xiang; Yu Dehong; Chao Minghao — 2026
Score: 5/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, treatment-target

Paper demonstrates cGAS-STING and mtDNA release as immunogenic triggers in tumor context, and describes NLRP3-relevant ionic dysregulation; however, no direct SAMHD1 involvement, no VDAC1 mechanistic detail, and no connection to dNTPase/haploinsufficiency or documented interferonopathy phenotypes (ME/CFS, AuDHD, poliosis)—represents general ion-homeostasis immunotherapy orthogonal to SAMHD1 pathophysiology.
DOI: 10.1021/acsnano.6c00358

Oxidative stress in neurodegeneration: from a simple insult to a dynamic regulator. (from Neurology/Neurodegenerative disease; the paper's focus on oxidative stress and nanocarrier BBB penetration could tangentially support therapeutic development for the CNS manifestations (AuDHD, ME/CFS post-viral exacerbation) but does not engage the immunological or SAMHD1-centric driving mechanisms.)
Zhang Lan; Zhai Xinyue; Yan Yalong; Xiang Lihong; Zhang Yue — 2026
Score: 5/10 | Pathways: POLG-mtDNA, mTOR-lysosomal, treatment-target

Review addresses oxidative stress and mitochondrial quality control (POLG-relevant oxidized mtDNA damage, mitophagy mechanisms) plus mTOR and lysosomal pathways, with emphasis on personalized antioxidant delivery strategies; however, lacks any SAMHD1, cGAS-STING, NLRP3, ISG15, or JAK-STAT mechanistic specificity required for direct relevance to the convergent interferon-mitochondrial syndrome in A565T haploinsufficiency.
DOI: 10.1080/13510002.2026.2654906

Jieduquyuziyin prescription for systemic lupus erythematosus: a system-level therapeutic strategy for immunological recalibration. (from Rheumatology/Immunology (SLE autoimmunity) and Traditional Chinese Medicine pharmacology, not genetics/rare disease or post-viral physiology)
Gan Yihong; Liu Jingqun; Zhou Shihui; Lin Ke; Wang Xinchang — 2026
Score: 5/10 | Pathways: NLRP3, JAK-STAT, IRF7-metabolic, mTOR-lysosomal, treatment-target, clinical-phenotype

SLE shares convergent immunometabolic dysregulation (NLRP3/JAK-STAT/mTOR/mitochondrial dysfunction/gut dysbiosis axis) with SAMHD1 A565T interferonopathy, but this paper addresses classical autoimmune SLE without SAMHD1 involvement, genetic haploinsufficiency, or type I interferon dominance; potentially relevant as phenocopy model or repurposable pathway-level therapeutic strategy (JAK inhibition, mTOR modulation, mitochondrial restoration) for post-viral/interferonopathy ME/CFS rather than direct mechanistic insight.
DOI: 10.1186/s13020-026-01397-x

🟢 Low Relevance (Score 3–4)

Potential specialty bridges — skim titles

The oxidative stress paradigm in arbovirus infections: mechanisms and therapeutic insights. (from Virology/Infectious Disease—arbovirus-focused review lacks integration with primary immunodeficiency genetics or type I interferonopathy spectrum.)
Ke Yee Chang; Lani Rafidah; Hassandarvish Pouya — 2026
Score: 3/10 | Pathways: NLRP3, mTOR-lysosomal, other

Arbovirus-ROS-NF-κB-mitochondrial dysfunction cascade overlaps tangentially with SAMHD1 haploinsufficiency pathology (NLRP3 activation, mitochondrial impairment), but lacks any mechanistic connection to dNTPase activity, cGAS-STING axis, VDAC1 escape, ISGylation-mediated mitophagy block, or the specific dGTP-driven convergent interferon-mitochondrial syndrome defining this family; arboviral redox-modulating therapeutics (NAC, polyphenols, Nrf2) do not address the upstream SAMHD1 deficiency or downstream STING/ISG15 dysregulation.
DOI: 10.1080/13510002.2026.2659994

Pathway Coverage This Week

treatment-target: 37 papers
cGAS-STING: 34 papers
VDAC1: 28 papers
NLRP3: 18 papers
POLG-mtDNA: 17 papers
ISG15-mitophagy: 16 papers
clinical-phenotype: 14 papers
JAK-STAT: 11 papers
AGS-spectrum: 6 papers
mTOR-lysosomal: 4 papers
IRF7-metabolic: 3 papers
poliosis-neural-crest: 2 papers
other: 2 papers
mtDNA leakage-VDAC1: 1 papers
senescence-EMT: 1 papers