SAMHD1 Research Digest — 2026-06-07¶
Generated by samhd1_monitor | Model: claude-sonnet-4-6
Summary: 21 papers evaluated | 9 high-relevance (≥7) | 6 medium (5–6) | 6 low (3–4) | 0 scored <3
🔴 High Relevance (Score 7–10)¶
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Mitochondrial DNA release and inflammation in mitochondrial disease pathogenesis. (from Mitochondrial disease / Genetics)
Szabo Marton; Lagos Daniel; Cross Emily; Collier Jack J; Horvath Rita — 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, NLRP3, POLG-mtDNA, ISG15-mitophagy, JAK-STAT, AGS-spectrum, ME-CFS, treatment-target, clinical-phenotype
This review directly covers the mechanistic chain central to SAMHD1 A565T pathogenesis—mtDNA release via mitochondrial membrane integrity loss (VDAC1), cGAS-STING activation, type I interferon/JAK-STAT signaling, and NLRP3 inflammasome engagement in primary mitochondrial diseases—and discusses therapeutic implications including cGAS-STING and NLRP3 inhibitors, making it highly relevant to all four mechanistic streams (PURPLE, BLUE, RED, GOLD) of the disease model.
DOI: 10.1093/brain/awag037
VDAC1 mediates LPS-induced T cell inflammation via mtDNA release and cGAS-STING activation. (from Critical care / sepsis immunology)
Yuqian Ren; Zhu Guangyao; Yucai Zhang; Yun Cui; Jie Gu — 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, NLRP3, treatment-target, ME-CFS
This paper directly demonstrates the VDAC1 oligomerization → mtDNA cytosolic release → cGAS-STING-TBK1 activation axis (the BLUE stream) in primary T cells, validates VBIT-12 as a pharmacological inhibitor of this pathway, and reports IL-18 elevation consistent with NLRP3 co-activation, making it highly mechanistically relevant to SAMHD1 haploinsufficiency pathophysiology where SAMHD1/VDAC1 interaction loss is proposed to drive the same cascade.
DOI: 10.1016/j.cellsig.2026.112642
Fingolimod increases cellular resistance to HIV-1 infection and limits viral reservoir size in peripheral CD4+ T-cells. (from Virology/HIV medicine)
Moraga Elisa; Climent Núria; Sánchez-Molina Alejandro; Vicens-Artés Sònia; Malen — 2026
Score: 7/10 | Pathways: dNTPase, treatment-target, ME-CFS, other
This paper directly demonstrates that SAMHD1 phosphorylation inhibition (via fingolimod) enhances dNTPase activity to restrict viral replication, providing mechanistic insight into how modulating SAMHD1 activity state — directly relevant to the haploinsufficiency context — affects dNTP pool dynamics and viral restriction, with fingolimod as a potential treatment modulator of the same SAMHD1 activity axis central to the disease mechanism.
DOI: 10.1371/journal.ppat.1014266
ALA-PDT Induces Apoptosis in HPV-transformed Cells through mtDNA Release-Mediated Activation of the cGAS-STING Pathway. (from Dermatology/photodynamic therapy)
Lei Shuangyi; Xu Rui; Deng Yuan; Feng Sining; Chen Yu — 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, VDAC1, treatment-target
This paper directly demonstrates the mechanistic sequence of mtDNA cytosolic release → cGAS-STING activation → apoptosis (confirmed by ρ0 depletion experiments), which is the core BLUE stream of the SAMHD1 haploinsufficiency mechanism, and pharmacological STING inhibition as a therapeutic target closely parallels the cGAS/STING inhibitor interventions (e.g., IMSB301) relevant to this disease.
DOI: 10.1016/j.pdpdt.2026.105534
Expanding roles of cGAS-STING signaling in neuroinflammation. (from Neurology/Neuroscience)
Feng Weixi; Aikedan Abulimiti; Sinha Subhash C; Gan Li — 2026
Score: 7/10 | Pathways: cGAS-STING, JAK-STAT, IRF7-metabolic, AGS-spectrum, ME-CFS, treatment-target
This review directly covers the cGAS-STING pathway (BLUE stream core mechanism) in neuroinflammation including canonical IFN-I induction, noncanonical nuclear roles, glial activation, blood-brain barrier integrity, and pharmacological inhibitors targeting cGAS/STING—all highly relevant to the SAMHD1 A565T interferonopathy mechanism where VDAC1-mediated cytosolic mtDNA fragments activate cGAS→cGAMP→STING→IRF3→IFN-I, and to the neurological phenotypes (AuDHD, ME/CFS, potential neurodegeneration) in the proband and family.
DOI: 10.1172/jci204550
Autoinflammatory syndromes of STING and TREX1 dysfunction. (from rare disease / genetics)
Park Debby J; Jones Kate M; Anderson Jessica B; Finck Amanda V; Miner Jonathan J — 2026
Score: 7/10 | Pathways: cGAS-STING, AGS-spectrum, dNTPase, treatment-target, clinical-phenotype
This review directly covers the cGAS-STING axis and its negative regulation by DNA-degrading enzymes (TREX1 paralleling SAMHD1's dNTPase role), STING gain-of-function vasculopathy, Aicardi-Goutières spectrum interferonopathies, and first-in-class small molecule therapeutics targeting this pathway—all directly mechanistically relevant to SAMHD1 haploinsufficiency-driven IFN-I overactivation via the BLUE stream (VDAC1→cGAS→STING→IRF3), though SAMHD1 itself is not discussed.
DOI: 10.1172/jci204549
Aspartate deficiency amplifies cGAS-STING signaling in antitumor immunity. (from Oncology/tumor immunology)
Liao Yuheng; Wang Hanze; Liu Hengxin; Chen Xi; Sun Renqiang — 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, JAK-STAT, dNTPase, treatment-target
This paper directly illuminates a mechanistic link between nucleotide pool imbalance (aspartate/pyrimidine depletion causing mtDNA replication stress and DSBs → cytosolic mtDNA release → cGAS-STING → IRF3 → type I IFN amplification via ZBP1 feedback loop) that mirrors the SAMHD1 haploinsufficiency mechanism where dNTP pool expansion (especially dGTP) perturbs mtDNA replication via POLG stalling and drives cGAS-STING-mediated interferonopathy — the novel ZBP1/RIPK1/3 positive feedback loop sustaining IRF3 phosphorylation is a clinically important amplification mechanism not previously mapped in the SAMHD1 disease model.
DOI: 10.1172/jci199716
Fueling the fire: aspartate deficiency primes and fuels STING activation. (from Oncology/tumor immunology)
Jiang Haitao; Wang Wenyan; Fu Yang-Xin — 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, dNTPase, ME-CFS, treatment-target
This paper directly addresses cGAS-STING pathway activation via mtDNA stress driven by nucleotide pool disruption (aspartate deficiency → pyrimidine depletion → mtDNA stress), which is mechanistically parallel to SAMHD1 haploinsufficiency causing dNTP pool imbalance → mtDNA stress → cGAS-STING activation, and introduces ZBP1/RIPK1/3 as a feed-forward amplifier of STING signaling relevant to understanding why interferonopathy is self-sustaining in this family.
DOI: 10.1172/jci206431
Mitochondrial protein COXFA4L3 (C15ORF48) confers resistance to DNA-damaging anticancer agents by repressing mitochondrial DNA damage responses. (from Oncology/Cancer Biology)
Takakura Yuki; Kawamura Seika; Hashiguchi Yui; Yamanaka Manami; Kurihara Yasuyuk — 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, VDAC1, treatment-target
This paper directly demonstrates the mtDNA damage → cytosolic mtDNA release via mPTP → cGAS-STING activation axis that is central to the BLUE stream of SAMHD1 haploinsufficiency pathophysiology, specifically showing that mtDNA damage and mPTP-mediated cytosolic release drives cGAS-STING-dependent cell death, with COXFA4L3 as a novel repressor of this pathway—directly relevant to understanding how SAMHD1's interaction with VDAC1/mPTP components leads to chronic IFN-I signaling.
DOI: 10.1038/s41598-026-54548-3
🟡 Medium Relevance (Score 5–6)¶
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GSDME-Mediated Pyroptosis and the mtDNA-cGAS-STING Pathway Drive Deoxynivalenol-Induced Porcine Intestinal Inflammatory Injury. (from Veterinary/Food toxicology and gastroenterology)
Zhou Fenfen; Li Jie; Li Mingxuan; Guo Chongwen; Mao Xiaoxiao — 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, VDAC1, POLG-mtDNA, other
This paper directly demonstrates the mechanistic sequence of mitochondrial membrane permeabilization → cytosolic mtDNA release → cGAS-STING activation driving chronic intestinal inflammation, which mirrors the BLUE pathway (VDAC1 macropore → mtDNA escape → cGAS-STING) central to SAMHD1 haploinsufficiency, though the trigger (GSDME/caspase-3 pyroptosis from mycotoxin) is distinct from SAMHD1-driven VDAC1 dysregulation.
DOI: 10.1021/acs.jafc.6c01535
Interstitial lung disease and the STING pathway. (from Pulmonology)
Velu Prasad Palani; Zhu Gaofeng; Mackenzie Karen J — 2026
Score: 6/10 | Pathways: cGAS-STING, JAK-STAT, IRF7-metabolic, AGS-spectrum, treatment-target, clinical-phenotype
This review directly covers the STING pathway in ILD, including SAVI and COPA syndrome which are type I interferonopathies mechanistically overlapping with SAMHD1 haploinsufficiency via cGAS-STING-IRF3 signaling, and discusses STING-targeted therapeutics relevant to Loop A of the disease mechanism, though it does not address SAMHD1, mtDNA, VDAC1, or the specific family phenotype.
DOI: 10.1172/jci204544
An Engineered Microbial Nanohybrid for Enhanced Ferroptosis Immunotherapy via Hypoxia-Responsive Hydrogen Sulfide Generation and Mitophagy Inhibition. (from Oncology/Nanomedicine)
Li Yuewei; Xu Shujing; Wang Guocheng; Song Zhangzhi; Zhang Shuqi — 2026
Score: 5/10 | Pathways: cGAS-STING, POLG-mtDNA, ISG15-mitophagy, BIK-cancer, treatment-target
The paper demonstrates mechanistic relevance to the disease model—specifically cytosolic mtDNA accumulation activating cGAS-STING and deliberate mitophagy inhibition (Mdivi-1) to sustain that signal—but is framed entirely as an oncology ferroptosis immunotherapy strategy in a murine mammary carcinoma model, with no connection to SAMHD1, haploinsufficiency, or the interferonopathy syndrome; the mechanistic insights into mtDNA–cGAS–STING amplification via mitophagy blockade are indirectly informative for understanding the RED/BLUE loop intersection in the disease mechanism.
DOI: 10.1021/acsnano.6c06383
Mitophagy in cisplatin-induced kidney injury: regulatory mechanisms and therapeutic targets. (from nephrology/oncology)
Yuan Cheng; Jiang Jinzhou; Ji Jinxing; Ni Lihua — 2026
Score: 5/10 | Pathways: NLRP3, ISG15-mitophagy, POLG-mtDNA, mTOR-lysosomal, other
This review covers PINK1/Parkin-dependent mitophagy, pyroptosis/NLRP3 inflammasome, and mitochondrial quality control mechanisms that are directly relevant to the RED-stream ISGylation-mediated mitophagy block and NLRP3 activation central to the disease model, but the cisplatin-AKI context is clinically unrelated and the paper does not address cGAS-STING, SAMHD1, or type I interferonopathy.
DOI: 10.1080/07853890.2026.2672141
Mitochondrial dysfunction in neurodegenerative disorders: mechanisms and therapeutic advances. (from Neurology/neurodegeneration)
Tong Yan; He Jing Na; Zhou Linbin; Zhang Jiaxin; Ho Bo Man — 2026
Score: 5/10 | Pathways: POLG-mtDNA, ISG15-mitophagy, VDAC1, mTOR-lysosomal, treatment-target, other
This review covers mitochondrial dynamics, quality control (mitophagy), oxidative phosphorylation defects, and mtDNA integrity—all mechanistically central to the PURPLE and RED streams of the SAMHD1 haploinsufficiency model—but does not engage with cGAS-STING, interferonopathy, NLRP3, or SAMHD1 itself, making it background context rather than directly actionable evidence.
DOI: 10.1186/s43556-026-00480-x
PRKN Ser131 phosphorylation promotes cigarette smoke-induced mitophagy impairment and epithelial cell senescence via MKK3/p38 MAPK activation: An in vitro and in vivo study. (from Pulmonology/COPD)
Hu Yajie; Liu Jianyu; Zhang Mengyu; Qu Jiajia; Hao Wenqiang — 2026
Score: 5/10 | Pathways: ISG15-mitophagy, other
This paper directly investigates Parkin (PRKN)/PINK1-dependent mitophagy impairment via a phosphorylation-mediated block, which is directly relevant to the RED stream where ISGylation of PINK1/Parkin blocks mitophagy, but the mechanism here is MKK3/p38 MAPK-driven rather than ISG15/interferonopathy-driven, making it an adjacent mechanistic parallel rather than a core pathway contribution.
DOI: 10.18332/tid/218816
🟢 Low Relevance (Score 3–4)¶
Potential specialty bridges — skim titles
Metabolic dysfunction-associated steatotic liver disease: pathogenesis and novel treatment options. (from hepatology)
Ren Ruizhe; Liang Xiao; Wei Xiyang — 2026
Score: 4/10 | Pathways: NLRP3, IRF7-metabolic, mTOR-lysosomal, urate-NLRP3, other
MASLD review touches on mitochondrial dysfunction, inflammasome/NLRP3 activation, and hepatic steatosis which are family phenotype-adjacent (hepatic steatosis listed explicitly, cholecystectomy clustering), but does not engage cGAS-STING, SAMHD1, ISG15, VDAC1, or interferonopathy mechanisms that would make it mechanistically relevant to the disease profile.
DOI: 10.1186/s43556-026-00486-5
A genomic structural equation modelling analysis of the shared genetic architecture of the aging spine. (from Orthopedic genetics / musculoskeletal genomics)
Chen Jianquan; Zhong Xingjie; Li Liping; Feng Peiyun; Duan Xiuping — 2026
Score: 3/10 | Pathways: dNTPase, other
SAMHD1 appears as a GWAS/TWAS susceptibility gene for aging spine traits (lumbar spinal stenosis, disc degeneration, sciatica) via genomic stability pathways, but the paper treats it purely as a statistical genomic signal without any mechanistic investigation of dNTPase function, interferonopathy, or the SAMHD1 p.A565T variant, making it tangentially relevant at best.
DOI: 10.1007/s00586-026-10039-7
Highly Efficient Lentiviral Transduction of Human iPSC-Derived Microglia and Macrophages (from Neuroscience/cell biology methods)
Goberdhan Srilakshmi; Czubala Magdalena; Thomas Sophie; Taylor Philip; Connor-Ro — 2026
Score: 3/10 | Pathways: dNTPase, other
This paper mentions SAMHD1 only as a lentiviral restriction factor in myeloid cells that is removed via VPX to improve transduction efficiency in iPSC-derived microglia, providing no mechanistic insight into SAMHD1 haploinsufficiency, dNTPase function, or any of the core interferon-mitochondrial pathways relevant to the A565T variant.
DOI: 10.64898/2026.05.23.727402
Insights into the therapeutic strategies for aging and aging-associated diseases. (from Geroscience/longevity medicine)
Dong Ruifang; Wu Qiming; Kan Juntao; Fu Caili; Sorrentino Vincenzo — 2026
Score: 3/10 | Pathways: mTOR-lysosomal, NLRP3, ISG15-mitophagy, other
This broad aging review touches on mitochondrial impairment, cellular senescence, autophagy (rapamycin/mTOR), and SASP—mechanisms that partially overlap with the SAMHD1 interferonopathy-mitochondrial cascade—but contains no direct engagement with cGAS-STING, NLRP3 inflammasome, VDAC1, ISG15, or SAMHD1, making it only tangentially relevant as background context.
DOI: 10.1038/s41392-026-02662-z
Nanozymes for Bone Regeneration: Mechanistic Insights into Immune and Metabolic Microenvironment Modulation. (from Biomaterials/Orthopedic tissue engineering)
Wang Yue; Song Meiyuan; Chen Shumeng; He Yang; Chen Shuxuan — 2026
Score: 3/10 | Pathways: NLRP3, other
This nanozyme review touches on NLRP3/NF-κB suppression and mitochondrial function restoration in the context of bone regeneration, which are peripheral overlaps with the disease mechanism, but the paper is fundamentally about biomaterial engineering for orthopedic repair with no connection to SAMHD1, interferonopathy, dNTP biology, or the family phenotype.
DOI: 10.2147/ijn.s607165
The homozygous founder Psmb8 variant of Nakajo-Nishimura syndrome/proteasome-associated autoinflammatory syndrome causes panniculitis-associated lipoatrophy and a shortened lifespan in mice. (from Rare disease / autoinflammatory immunology)
Hara Tomoyuki; Kinoshita Akira; Hamazaki Jun; Hemmi Hiroaki; Kato Takashi — 2026
Score: 3/10 | Pathways: NLRP3, JAK-STAT, AGS-spectrum, clinical-phenotype, other
This paper describes a proteasome-dysfunction autoinflammatory syndrome (NNS/PRAAS) driven by PSMB8 variants, which causes type I interferonopathy features (periodic fever, lipoatrophy, cytokine activation) via a proteasome-ubiquitin pathway mechanistically distinct from the SAMHD1/cGAS-STING/NLRP3 axes central to SAMHD1 A565T haploinsufficiency, making it a tangential interferonopathy model with limited direct pathway overlap.
DOI: 10.1038/s41598-026-51190-x
Pathway Coverage This Week¶
treatment-target: 12 paperscGAS-STING: 11 papersother: 11 papersPOLG-mtDNA: 9 papersNLRP3: 8 papersVDAC1: 6 papersISG15-mitophagy: 6 papersdNTPase: 6 papersJAK-STAT: 5 papersAGS-spectrum: 5 papersME-CFS: 5 papersclinical-phenotype: 4 papersmTOR-lysosomal: 4 papersIRF7-metabolic: 3 papersBIK-cancer: 1 papersurate-NLRP3: 1 papers