Skip to content

AGS-spectrum

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

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

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

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