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

SAMHD1 Research Digest — 2026-05-31

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

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

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🔴 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

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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