SAMHD1 Research Digest — 2026-04-22¶

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

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

🔴 High Relevance (Score 7–10)¶

Added to Zotero automatically

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

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

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

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

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

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

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

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

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

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

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

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

🟡 Medium Relevance (Score 5–6)¶

Review and add to Zotero manually if warranted

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

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

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

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

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

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

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

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

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

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

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

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

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

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

🟢 Low Relevance (Score 3–4)¶

Potential specialty bridges — skim titles

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

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

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

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

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

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

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

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

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

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

Pathway Coverage This Week¶

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

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

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

🔴 High Relevance¶

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

🟡 Medium Relevance¶

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

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

🟢 Low Relevance¶

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

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

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

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

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

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

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

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

🔴 High Relevance¶

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

🟡 Medium Relevance¶

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

🟢 Low Relevance¶

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

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

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

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

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

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

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

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

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

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

No new papers above threshold in this run.