SAMHD1 Research Digest — 2026-05-17¶
Generated by samhd1_monitor | Model: claude-sonnet-4-6
Summary: 12 papers evaluated | 7 high-relevance (≥7) | 3 medium (5–6) | 2 low (3–4) | 0 scored <3
🔴 High Relevance (Score 7–10)¶
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NOX2 inhibitor baicalein alleviates rheumatoid arthritis and inactivating mitochondrial oxidative stress-mediated cGAS-STING signaling in fibroblast-like synoviocytes. (from Rheumatology)
Wang Rui; Fang Weiming; Qiao Yansheng; Zhang Xin; Gao Yuan — 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, treatment-target, clinical-phenotype, other
This paper directly characterizes the NOX2→mtROS→VDAC1 oligomerization→mtDNA release→cGAS-STING axis in rheumatoid arthritis fibroblast-like synoviocytes, precisely mapping the BLUE-stream mechanism (VDAC1 macropore → cytosolic mtDNA → cGAS → STING → IFN-I) that is central to the SAMHD1 A565T interferonopathy model, while also identifying baicalein as a pharmacological intervention point and linking it to a clinically relevant autoimmune phenotype present in the family.
DOI: 10.1016/j.phymed.2026.158268
Macrophage TRPML1 ameliorates post-myocardial infarction inflammation by blocking VDAC1 oligomerization to prevent ferroptosis and cGAS-STING activation. (from Cardiology (post-myocardial infarction inflammation and cardiac repair))
Zhao Xiuye; Wang Jia; Wang Zhenru; Du Haonan; Li Hongda — 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, NLRP3, POLG-mtDNA, treatment-target, mTOR-lysosomal
This paper directly demonstrates that VDAC1 oligomerization drives mtDNA cytosolic escape → cGAS-STING activation → pro-inflammatory cytokine storm in macrophages, and identifies VDAC1 inhibition (NSC 15364) as a therapeutic rescue strategy — mechanistically identical to the BLUE stream of the SAMHD1 A565T syndrome (SAMHD1/VDAC1 interaction loss → VDAC1 macropore → cytosolic mtDNA → cGAS → STING → IFN-I), making it highly relevant as both mechanistic validation and a potential treatment target.
DOI: 10.1016/j.freeradbiomed.2026.05.006
Tempol alleviates autoimmune uveitis by targeting the oxidative stress-mediated cGAS-STING-NF-kB signaling pathway to restore M1/M2 macrophage polarization balance. (from Ophthalmology/Autoimmune uveitis)
Xu Shuqin; Feng Jiaye; Peng Yuan; Xu Furu; Liu Yunfeng — 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, ISG15-mitophagy, treatment-target, other
This paper directly demonstrates the oxidative stress → mitochondrial damage → cytosolic mtDNA release → cGAS-STING-NF-κB → IFN-β → M1 macrophage polarization axis with impaired PINK1/Parkin mitophagy, which maps precisely onto the BLUE and RED streams of the SAMHD1 haploinsufficiency mechanism, and identifies Tempol (a superoxide dismutase mimetic/ROS scavenger) and STING inhibitor H-151 as therapeutic interventions that restore mitophagy flux and suppress interferon output—directly actionable for the family's convergent interferon-mitochondrial syndrome.
DOI: 10.1016/j.intimp.2026.116798
Mitochondrial dysfunction due to myeloid TFAM loss limits senolytic efficacy in allergic airway inflammation. (from Pulmonology/Allergy)
Nguyen Jackie; Van Courtney; Olverson Zianne A; Sampath Neil; Posham Lalithya — 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, VDAC1, ISG15-mitophagy, other
This paper directly demonstrates that TFAM loss causes cytosolic mtDNA accumulation activating cGAS-STING signaling in macrophages, driving senescence-associated inflammation — a mechanistic parallel to the SAMHD1 BLUE pathway where VDAC1 macropore release of mtDNA fragments activates cGAS-STING-IRF3-IFN-I, and the finding that mitochondrial DNA maintenance failure amplifies innate immune activation is directly relevant to understanding how SAMHD1 haploinsufficiency sustains chronic interferonopathy via cytosolic mtDNA.
DOI: 10.1093/ajrcmb/aanag101
MSTO1 modulates RAD51 activity to safeguard mitochondrial DNA integrity and control immune responses. (from mitochondrial biology / rare neuromuscular disease)
Cheng Kaiqi; Xu Zhanzhan; Liu Jiansong; Pan Yichen; Nie Chen — 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, VDAC1, ME-CFS, other
MSTO1 deficiency causes RAD51-mediated mtDNA damage, BAX/BAK-dependent mtDNA leakage activating cGAS-STING inflammation—directly paralleling the BLUE stream (VDAC1 macropore → cytosolic mtDNA → cGAS → IFN-I) and POLG-mtDNA integrity mechanisms central to the SAMHD1 A565T interferonopathy model, offering a novel upstream regulator of the same mtDNA-immune axis.
DOI: 10.1038/s41417-026-01032-9
α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication. (from Neuroscience/neurodegeneration)
Chakraborty Ranabir; Maya Stephanie; Testa Veronica; Montero-Muñoz Jara; Nonaka * — 2026
Score: 7/10* | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, mTOR-lysosomal, other
This paper directly demonstrates the mechanistic chain of mitochondrial damage → cytosolic mtDNA release → cGAS-STING-IRF3 activation that constitutes Loop A/B of the SAMHD1 haploinsufficiency model, and further shows that damaged mitochondria are transferred intercellularly and degraded via lysosomal pathways, with NF-κB and IRF3 driving inflammatory amplification—all core molecular players in the disease mechanism, albeit in a synucleinopathy context rather than SAMHD1-specific.
DOI: 10.1038/s41467-026-73136-7
Mechano-metabolic feedback connects tissue fluidity to mitochondrial DNA-dependent immunity in breast cancer. (from Oncology / tumor mechanobiology)
Palamidessi Andrea; Frittoli Emanuela; Corada Monica; Martini Emanuele; Barzaghi — 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, BIK-cancer, other
This paper directly demonstrates a mtDNA-release → cGAS-STING → innate immune hyperinflammation axis in cancer, mediated by BAX/BAK outer mitochondrial membrane permeabilization and GASDERMIN A oligomerization, which is mechanistically analogous to the SAMHD1/VDAC1 macropore → cytosolic mtDNA → cGAS-STING loop (Loop A/B) in the disease model, and provides novel upstream (mechano-metabolic, mitochondrial fission via AMPK-AKAP1-DRP1) and downstream (tumor immunogenicity, checkpoint sensitivity) context relevant to SAMHD1 haploinsufficiency-driven interferonopathy and cancer susceptibility.
DOI: 10.1038/s41467-026-71795-0
🟡 Medium Relevance (Score 5–6)¶
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cGAS-STING Signalling in the tumour microenvironment: Implications for immune surveillance and therapeutic strategies. (from Oncology / tumour immunology)
Al-Adayleh Teeb Yasir Mahmoud; Ahmad Waqas; Rahiman Siti Sarah Fazalul; Murugaiy — 2026
Score: 6/10 | Pathways: cGAS-STING, JAK-STAT, POLG-mtDNA, mTOR-lysosomal, treatment-target, other
This review covers the cGAS-STING pathway in depth—including mtDNA release as a trigger, STING-NF-κB crosstalk, autophagy interactions, and pharmacological modulators—all directly relevant to the BLUE stream of the SAMHD1 interferonopathy mechanism, but is framed entirely around oncology/TME rather than monogenic interferonopathy or SAMHD1 haploinsufficiency.
DOI: 10.1016/j.intimp.2026.116832
O-GlcNAcylation of p66Shc drives senescence associated secretory phenotype via mitochondrial DNA release in gestational diabetes mellitus†. (from Obstetrics/reproductive medicine)
Zhu Hengxuan; Ji Lulu; Lai Rujie; Nai Yaru; Yang Xiting — 2026
Score: 6/10 | Pathways: cGAS-STING, POLG-mtDNA, pregnancy-fetal, other
This paper directly demonstrates cytoplasmic mtDNA release activating cGAS/STING to drive senescence-associated secretory phenotype and inflammation in a gestational/placental context, which is mechanistically adjacent to the BLUE stream (VDAC1→mtDNA→cGAS→STING→IFN-I) and relevant to the pregnancy-fetal phenotype dimension of the family profile, though the driver is p66Shc O-GlcNAcylation under high glucose rather than SAMHD1 haploinsufficiency.
DOI: 10.1093/biolre/ioag090
Recent advances in dual-function fluorescent ligands targeting mitochondrial DNA G-Quadruplexes for Cancer Theranostics. (from oncology/chemical biology)
Hu Ming-Hao — 2026
Score: 6/10 | Pathways: cGAS-STING, POLG-mtDNA, NLRP3, VDAC1, treatment-target, other
This review is adjacently relevant because mtG4-targeting ligands directly perturb mitochondrial DNA integrity and dNTP pool dynamics (core to SAMHD1 haploinsufficiency pathology), activate cGAS-STING via cytosolic mtDNA release, and trigger NLRP3-associated PANoptosis—all three major mechanistic streams (BLUE, PURPLE, GOLD) of the SAMHD1 interferonopathy model—while the cancer theranostics framing connects to the family's oncological phenotypes (prostate, myeloma, endometrial cancers) and offers potential treatment-target insights via mitochondrial metabolic collapse strategies.
DOI: 10.1016/j.bmc.2026.118697
🟢 Low Relevance (Score 3–4)¶
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A prognostic model based on nucleotide metabolism genes in osteosarcoma. (from oncology)
Ju Songli; Tao Lu; Li Xuyan; Huang Nijiao; Ke Xixian — 2026
Score: 4/10 | Pathways: dNTPase, BIK-cancer, IRF7-metabolic, other
SAMHD1 is included as one of seven nucleotide metabolism genes in an osteosarcoma prognostic model, confirming its role in metabolic reprogramming and tumor suppression, but the paper does not investigate SAMHD1 mechanism, haploinsufficiency, dNTPase activity, or any of the core interferon-mitochondrial pathways relevant to this disease profile.
DOI: 10.1007/s12672-026-05036-7
A cell-impermeable kinase inhibitor uncovers outside-in signaling pathways that promote HIV-1 infection. (from Virology/HIV research)
Vinzant Kelsey; Cheshenko Natalia; Pan Heng; Cutler Ronald; Buckler Joshua N — 2026
Score: 4/10 | Pathways: dNTPase, other
The paper touches on SAMHD1 only as a CDK-phosphorylation target (phospho-SAMHD1 inactivating its dNTPase activity to promote HIV infection), which is tangentially related to the core disease mechanism of reduced SAMHD1 dNTPase activity, but the study is focused on HIV entry/infection mechanisms and exofacial signaling rather than interferonopathy, mitochondrial dysfunction, or any pathway directly relevant to the A565T haploinsufficiency syndrome.
DOI: 10.1128/jvi.00160-26
Pathway Coverage This Week¶
other: 11 paperscGAS-STING: 10 papersVDAC1: 8 papersPOLG-mtDNA: 8 paperstreatment-target: 5 papersmTOR-lysosomal: 3 papersNLRP3: 2 papersISG15-mitophagy: 2 papersBIK-cancer: 2 papersdNTPase: 2 papersclinical-phenotype: 1 papersME-CFS: 1 papersJAK-STAT: 1 paperspregnancy-fetal: 1 papersIRF7-metabolic: 1 papers