SAMHD1 Research Digest — 2026-06-28¶
Generated by samhd1_monitor | Model: claude-sonnet-4-6
Summary: 12 papers evaluated | 6 high-relevance (≥7) | 5 medium (5–6) | 1 low (3–4) | 0 scored <3
🔴 High Relevance (Score 7–10)¶
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Fibroblast Mitochondrial Ca2+ Overload Drives Skin Fibrosis via mtDNA Leakage and cGAS-STING Activation in Systemic Sclerosis. (from Rheumatology/connective tissue disease (systemic sclerosis))
Zhang Xiaoyun; Wang Yingyu; Huang Hai; Guo Xinyi; Ye Wenjing — 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, treatment-target, other
This paper directly demonstrates the VDAC1 oligomerization → cytosolic mtDNA leakage → cGAS-STING activation axis in a fibrotic disease context, mechanistically validating the BLUE stream of the SAMHD1 haploinsufficiency model, and identifies VDAC1 inhibition and STING inhibition (H-151) as therapeutic targets with in vivo efficacy—highly actionable for the treatment-target framework.
DOI: 10.1002/art.70261
Delphinidin targets voltage-dependent anion channel 1 to inhibit ferroptosis and protect against retinal photochemical damage. (from Ophthalmology/retinal biology)
Wang Hansheng; Li Keyi; Pu Haomou; Xiong Yaoyao; Luo Dan — 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, treatment-target
This paper directly demonstrates the VDAC1 oligomerization → cytosolic mtDNA leakage → cGAS-STING activation axis that is central to the BLUE stream of the disease mechanism, and identifies delphinidin as a direct VDAC1-targeting compound that interrupts this cascade, making it highly relevant as both a mechanistic validation and a potential therapeutic lead analogous to VBIT-4.
DOI: 10.1016/j.phymed.2026.158455
Interrupting a mitochondrial DNA-driven innate immune circuit attenuates hepatic tissue remodeling and fibrotic architecture in experimental steatohepatitis. (from Hepatology)
Hamad Rabab S; Mohammed Sura Akram; Hasan Waseem Ali; AbuoHashish Norhan Ahmed; * — 2026
Score: 8/10* | Pathways: cGAS-STING, NLRP3, ISG15-mitophagy, IRF7-metabolic, POLG-mtDNA, treatment-target, clinical-phenotype
This paper directly interrogates the mtDNA-cGAS-STING-IRF3-IFN-β axis combined with NLRP3/IL-1β inflammasome and mitophagy (PINK1/Parkin) blockade in a metabolic liver disease model—mapping precisely onto the BLUE, RED, and PURPLE mechanistic streams of the SAMHD1 A565T interferonopathy, and demonstrating that dual upstream (mitophagy enhancement via urolithin A) plus downstream (STING inhibition via C176) targeting produces synergistic multi-domain control, providing directly translatable therapeutic logic for the hepatic steatosis phenotype documented in the family.
DOI: 10.1016/j.tice.2026.103733
Mitochondria-associated endoplasmic reticulum membrane (MAM): roles in innate immunity dysregulation. (from Cell biology / organelle biology)
Zhang Qingqi; Gao Junyan; Yang Yiting; Guo Ping; Gao Huiqin — 2026
Score: 8/10 | Pathways: cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy, POLG-mtDNA, treatment-target
This review directly covers the MAM as a hub integrating cGAS-STING activation, NLRP3 inflammasome, mtDNA release via mitochondrial fission/fusion dynamics, and mitophagy/autophagy flux—all four core pathways (PURPLE, BLUE, RED, GOLD) of the SAMHD1 A565T disease mechanism—and explicitly identifies the self-reinforcing cycle between MAM dysfunction and innate immune overactivation that underlies the proposed interferonopathy, making it highly mechanistically relevant even without direct SAMHD1 mention.
DOI: 10.1186/s12964-026-03013-9
Suppression of STING by Acacetin attenuates renal fibrosis via balancing mitophagy and protective nucleoid-phagy. (from Nephrology/Traditional Chinese Medicine pharmacology)
Gao Yujiu; Mu Linjie; Liu Chen; Zhao Yue; Cai Rui — 2026
Score: 7/10 | Pathways: cGAS-STING, ISG15-mitophagy, VDAC1, treatment-target, mTOR-lysosomal
This paper directly investigates STING inhibition restoring mitophagy flux and mitochondrial quality control in a fibrotic context, directly relevant to the BLUE and RED pathway loops where cGAS-STING activation and mitophagy blockade drive the interferonopathy cycle in SAMHD1 haploinsufficiency; Acacetin's direct STING binding (Kd=1.57µM) and restoration of autophagic/mitophagic flux represent a novel small-molecule treatment-target insight.
DOI: 10.1016/j.jep.2026.122094
A negative regulator of mitochondrial complex I assembly adapts respiration to cellular energy demand. (from Mitochondrial cell biology / bioenergetics)
Li Zhirong; Chen Nuo; Zhou Caixia; Xu Lingna; Wang Xiyuan — 2026
Score: 7/10 | Pathways: cGAS-STING, POLG-mtDNA, VDAC1, other
TMEM141 regulates Complex I assembly and its deficiency causes oxidative mtDNA damage and mtDNA release activating cGAS-STING, directly engaging the BLUE stream of the disease mechanism where cytosolic mtDNA fragments drive cGAS→STING→IRF3→IFN-I, while the Complex I/OXPHOS connection links to the mitochondrial dysfunction central to the PURPLE and RED streams, offering a novel regulatory node (TMEM141/TIMMDC1/AFG3L2/YME1L1 axis) upstream of mtDNA escape.
DOI: 10.1016/j.molcel.2026.06.018
🟡 Medium Relevance (Score 5–6)¶
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Role and mechanism of nitric oxide-regulated cGAS/STING pathway-mediated inflammatory response in hypoglycemia-induced coronary artery endothelial cell injury. (from Cardiology/Endocrinology)
Luo Wenping; Wei Xiao; Xiao Qian — 2026
Score: 6/10 | Pathways: cGAS-STING, POLG-mtDNA, VDAC1, clinical-phenotype, treatment-target
This paper demonstrates a mechanistic link between mitochondrial damage, mtDNA release, and cGAS/STING pathway activation in coronary endothelial cells—directly overlapping with the BLUE and PURPLE streams of the SAMHD1 haploinsufficiency model—and validates STING inhibition as a cardioprotective strategy, which is relevant to the cardiology clinical context of the family phenotype.
DOI: 10.1371/journal.pone.0350983
cGAS-STING Pathway Mediates Retinal Pigmental Epithelial Dysfunction in Diabetic Retinopathy. (from Ophthalmology/Retinal medicine)
Zhu Zhaoqi; Qiu Aowang; Wang Ningyu; Zhu Ziyu; Yin Wenjie — 2026
Score: 6/10 | Pathways: cGAS-STING, VDAC1, POLG-mtDNA, treatment-target
This paper directly demonstrates the mechanistic link between mitochondrial DNA leakage, cGAS-STING pathway activation, and downstream inflammation in a non-immune tissue context, validating the BLUE stream mechanism (mtDNA → cGAS → STING → inflammation) and showing STING inhibition as a pharmacological strategy, which is highly relevant to the core interferonopathy mechanism of SAMHD1 haploinsufficiency, though the disease context (diabetic retinopathy) is not directly related to the family phenotype.
DOI: 10.2337/db25-0128
GPAM mediates mitochondrial dysfunction and the progression of alcoholic liver disease through lipid remodeling. (from Hepatology)
Zhan Zibin; Liu Xuewen; Li Zehua; Qiao Xueyan; Li Shuo — 2026
Score: 6/10 | Pathways: cGAS-STING, ISG15-mitophagy, VDAC1, NLRP3, clinical-phenotype
This paper directly demonstrates that ceramide accumulation and cardiolipin loss disrupt mitochondrial dynamics and impair mitophagy, releasing mitochondrial DNA that activates cGAS-STING-driven inflammation—mechanistically mirroring the BLUE and RED pathway streams in SAMHD1 haploinsufficiency, and invoking ceramide (a named molecular player) alongside impaired mitophagy, though the context is alcoholic liver disease rather than interferonopathy.
DOI: 10.1126/sciadv.aef1896
Neuronal YTHDF2 suppresses innate immune activation in Aβ pathology by promoting m<sup>6</sup>A-dependent decay of cytosolic mitochondrial mRNAs. (from Neuroscience/Alzheimer's disease research)
Pan Wenqi; Yang Lin; Zhang Yao; Chen Yan; Xu Yuesi — 2026
Score: 6/10 | Pathways: cGAS-STING, JAK-STAT, ME-CFS, AGS-spectrum, other
This paper describes cytosolic mitochondrial RNA fragments activating innate immune signaling (RIG-I-MAVS → IFN-β → JAK-STAT neuroinflammation), a parallel mechanism to the VDAC1/cGAS-STING axis in the disease profile where cytosolic mt-derived nucleic acids drive type I interferon responses, reinforcing the concept that mitochondrial nucleic acid escape is a convergent driver of interferonopathy relevant to the SAMHD1 syndrome's neurological and inflammatory phenotypes.
DOI: 10.1126/sciadv.adz0887
RBM10 Deficiency Promotes Anti-PD-1 Resistance in LUAD via STING Alternative Splicing-Driven CCL7 Signaling and Macrophage Polarization. (from Oncology/thoracic)
Gao Weitong; Wang Ruqiong; An Bo; Qi Lishuang; Jing Zihan — 2026
Score: 5/10 | Pathways: cGAS-STING, other
This paper identifies a STING alternative splicing mechanism (exon 3 exclusion) that modulates cGAS-STING signaling output and feeds into a mtDNA-cGAS-STING positive feedback loop via mitochondrial transfer, which is adjacent to the BLUE and PURPLE streams of the SAMHD1 A565T disease mechanism, but the context is lung adenocarcinoma immunotherapy resistance rather than interferonopathy or SAMHD1 haploinsufficiency.
DOI: 10.1002/advs.202522159
🟢 Low Relevance (Score 3–4)¶
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The transcription factor IRF8 drives tumor-specific exhaustion in CD8+ T cells. (from Oncology/Tumor Immunology)
Ongaro Marco; Thouenon Romane; Crespo Isaac; Dumez Alexandre; Charmoy Mélanie — 2026
Score: 3/10 | Pathways: JAK-STAT, other
The paper identifies IRF8 as a tumor-specific regulator of CD8+ T cell exhaustion suppressed by sustained IFN-I signaling, which has indirect relevance to the SAMHD1 disease context via the JAK-STAT/IFN-I axis, but does not engage any core pathways (cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy, dNTPase) and focuses on tumor immunology rather than interferonopathy, mitochondrial dysfunction, or the family phenotypes described.
DOI: 10.1084/jem.20252115
Pathway Coverage This Week¶
cGAS-STING: 11 papersVDAC1: 8 papersPOLG-mtDNA: 7 paperstreatment-target: 7 papersother: 5 papersISG15-mitophagy: 4 papersNLRP3: 3 papersclinical-phenotype: 3 papersJAK-STAT: 2 papersIRF7-metabolic: 1 papersmTOR-lysosomal: 1 papersME-CFS: 1 papersAGS-spectrum: 1 papers