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 paperscGAS-STING: 34 papersVDAC1: 28 papersNLRP3: 18 papersPOLG-mtDNA: 17 papersISG15-mitophagy: 16 papersclinical-phenotype: 14 papersJAK-STAT: 11 papersAGS-spectrum: 6 papersmTOR-lysosomal: 4 papersIRF7-metabolic: 3 paperspoliosis-neural-crest: 2 papersother: 2 papersmtDNA leakage-VDAC1: 1 paperssenescence-EMT: 1 papers