SAMHD1 Research Digest — 2026-04-26
Generated by samhd1_monitor | Model: claude-sonnet-4-6
Summary: 10 papers evaluated | 4 high-relevance (≥7) | 5 medium (5–6) | 1 low (3–4) | 0 scored <3
🔴 High Relevance (Score 7–10)
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TH5487 specifically targets NLRP3 in FCAS patients resistant to MCC950. (from Autoinflammatory/rare disease (FCAS - Familial Cold Autoinflammatory Syndrome))
Lackner Angela; Picucci Sofia I; Jiang Wenjin; Onyuru Janset; Campos Melissa — 2026
Score: 8/10 | Pathways: NLRP3, POLG-mtDNA, cGAS-STING, treatment-target, ME-CFS
This paper directly addresses NLRP3 inflammasome inhibition via a novel hOGG1/oxidized-mtDNA sensing mechanism, demonstrates cryo-EM evidence of NLRP3-mitochondrial DNA association, shows TH5487 works where MCC950 fails (critical for treatment-resistant cases), and reveals that NLRP3 inhibition simultaneously increases type I interferon responses—all highly relevant to the PURPLE and BLUE pathways of the SAMHD1 haploinsufficiency mechanism where ox-mtDNA drives NLRP3 activation (Loop B) and cGAS-STING drives IFN-I (Loop A).
DOI: 10.1038/s42003-026-10008-2
Sesamin ameliorates high-fat diet-induced inflammation and metabolic dysfunction in pregnant uterine smooth muscle via cGAS-STING inhibition. (from Obstetrics/maternal-fetal medicine)
Xu Chenyi; Li Xuan; Yang Chen; Xing Ting; Yang Longtao — 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, POLG-mtDNA, pregnancy-fetal, treatment-target, IRF7-metabolic
This paper directly demonstrates the mtDNA leakage → cGAS-STING → IL-1β/IL-18 axis in a metabolic-inflammatory context with mitochondrial dysfunction, and identifies sesamin as a STING inhibitor that blocks this pathway — mechanistically overlapping with the BLUE and PURPLE streams of the SAMHD1 syndrome, while the pregnancy/uterine context is relevant to the obstetric phenotype dimension of the family.
DOI: 10.1016/j.phymed.2026.158182
TREM2 & senescent macrophages fuel inflammaging and metabolic dysfunction-associated steatotic liver disease. (from Hepatology/Geroscience)
Salladay-Perez Ivan A; Avila Itzetl; Estrada Lizeth; Alexandru Andreea C; Ponce * — 2026
Score: 7/10* | Pathways: cGAS-STING, NLRP3, VDAC1, JAK-STAT, IRF7-metabolic, POLG-mtDNA, mTOR-lysosomal, clinical-phenotype, treatment-target
This paper directly demonstrates that cytosolic mitochondrial DNA drives type I interferon signaling in senescent macrophages causing MASLD and inflammaging—mechanistically overlapping with the BLUE (cGAS-STING via mtDNA escape) and GOLD (liver/metabolic) streams of the SAMHD1 A565T syndrome, and the hepatic steatosis and cholecystectomy clustering phenotypes tracked in the family, with senolytic treatment as a novel therapeutic angle.
DOI: 10.1038/s43587-026-01101-6
Efficacy of JAK1/2 inhibitors in AGS genes-related interferonopathies: A multicenter retrospective observational study with treated vs untreated comparison. (from Pediatric neurology / rare disease genetics)
G. Marinella; Ylenia Vaia; Davide Politano; J. Galli; F. Nicita — Molecular genetics and metabolism 2026
Score: 7/10 | Pathways: JAK-STAT, AGS-spectrum, treatment-target, cGAS-STING, ISG15-mitophagy, ME-CFS, clinical-phenotype
This multicenter retrospective study directly evaluates baricitinib and ruxolitinib (JAK1/2 inhibitors) in AGS-related type I interferonopathies—the same therapeutic class most relevant to SAMHD1 haploinsufficiency-driven IFN-I overproduction—and critically notes that pathogenetic complexity extends beyond JAK-STAT, implying residual disease burden from parallel NLRP3/VDAC1/ISG15 streams that mirror the multi-loop mechanism of the documented family syndrome.
DOI: 10.1016/j.ymgme.2026.109907
🟡 Medium Relevance (Score 5–6)
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MRE11A Regulates Sepsis Through the mtDNA/STING Pathway of T Lymphocyte Apoptosis (from Pediatric critical care / sepsis immunology)
Wei Zhixin; Wang Feifei; Qin Pengji; Yang Zhiyong — 2026
Score: 6/10 | Pathways: cGAS-STING, POLG-mtDNA, ME-CFS, other
This paper directly demonstrates the mtDNA-cytosol → cGAS → STING axis driving T lymphocyte apoptosis via MRE11A loss, mechanistically paralleling the BLUE stream in SAMHD1 haploinsufficiency where cytosolic mtDNA fragments activate cGAS-STING-IRF3-IFN-I, with the added implication that MRE11A-mediated mtDNA containment failure (analogous to VDAC1 macropore-driven mtDNA escape) amplifies cGAS-STING signaling and immune exhaustion relevant to post-viral ME/CFS and immunodysfunction phenotypes in the family.
DOI: 10.21203/rs.3.rs-9414184/v1
18-β-glycyrrhetinic acid facilitates nuclear-mitochondrial communications to alleviate oxidative stress through HMGB1-cGAS-Mul1 axis in tendinopathy. (from Orthopaedics/musculoskeletal biology)
Gao Yuan-Yuan; Sun Wen-Shuang; Sun Zi-Ying; Wang Jun-Rui; Lv Zhong-Yang — 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, treatment-target, other
This paper directly characterizes a novel cGAS degradation mechanism via Mul1 ubiquitin ligase and HMGB1 methylation that suppresses cGAS-STING-NLRP3 signaling under oxidative stress—highly relevant as a potential therapeutic axis for the BLUE and PURPLE streams of the SAMHD1 haploinsufficiency syndrome, though the clinical context (tendinopathy) is entirely orthogonal to the family phenotype.
DOI: 10.1186/s12967-026-08091-4
Towards effective targeted therapies in morphea. (from Dermatology)
Amanda M Saracino; L. Iyengar; M. Nikpour — Italian journal of dermatology and venereology 2026
Score: 6/10 | Pathways: JAK-STAT, AGS-spectrum, cGAS-STING, treatment-target, clinical-phenotype
Morphea is characterized here as a type I interferonopathy enriched for IFN-I pathways, directly overlapping the BLUE/RED streams of the SAMHD1 mechanism, and JAK inhibitors (baricitinib, ruxolitinib class) are flagged as emerging treatments—the same class relevant to managing SAMHD1-driven interferonopathy—making this an adjacent clinical phenotype with shared molecular architecture and therapeutic implications.
DOI: 10.23736/S2784-8671.25.08413-0
Targeting cytokine pathways: the role of biologics in autoinflammatory disorders (from Rheumatology/rare disease)
T. Koga — Expert Review of Clinical Immunology 2026
Score: 6/10 | Pathways: NLRP3, JAK-STAT, AGS-spectrum, treatment-target, clinical-phenotype, IRF7-metabolic
This review directly covers interferonopathies and inflammasomopathies including their molecular mechanisms (IL-1/NLRP3, JAK-STAT/type I IFN) and therapeutic targeting with JAK inhibitors and IL-1 biologics, which are directly relevant to the SAMHD1 haploinsufficiency syndrome's dual NLRP3 and type I interferonopathy streams and potential treatment strategies, though SAMHD1 itself is not mentioned.
DOI: 10.1080/1744666X.2026.2625277
Discovering patterns in the pathologic significance of non-missense deleterious variants in RELA. (from Clinical Immunology / Rare Autoinflammatory Disease)
H. Hayakawa; M. Tsumura; Takanori Utsumi; H. Nihira; Wei-Te Lei — The Journal of allergy and clinical immunology 2026
Score: 5/10 | Pathways: JAK-STAT, AGS-spectrum, clinical-phenotype, other
RELA haploinsufficiency vs. dominant-negative distinction with type I interferonopathy overlap is conceptually analogous to SAMHD1 haploinsufficiency mechanisms, and the identification of DN variants driving interferonopathy beyond HI phenotypes parallels the SAMHD1 heterozygous pathogenic framework, but RELA/NF-κB is a parallel inflammatory axis not directly in the SAMHD1 mechanistic streams (cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy).
DOI: 10.1016/j.jaci.2026.01.020
🟢 Low Relevance (Score 3–4)
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Systematic discovery of pro- and anti-HIV host factors in primary human CD4+ T cells. (from virology)
Rathore Ujjwal; Dugan Eli; Thornton Hunter; Kumar Vigneshwari Easwar; Dajani Ram — 2026
Score: 3/10 | Pathways: dNTPase, other
This paper studies HIV host factors in CD4+ T cells using CRISPR screens and identifies restriction factors including cyclophilin paralogs and viral entry modulators, tangentially relevant only because SAMHD1 is a known HIV restriction factor (dNTPase/Vpx target) but the paper does not study SAMHD1, its dNTPase activity, or any of the core cGAS-STING/NLRP3/mitochondrial pathways relevant to the A565T haploinsufficiency syndrome.
DOI: 10.1016/j.cell.2026.03.046
Pathway Coverage This Week
cGAS-STING: 7 paperstreatment-target: 7 papersNLRP3: 5 papersJAK-STAT: 5 papersclinical-phenotype: 5 papersPOLG-mtDNA: 4 papersAGS-spectrum: 4 papersother: 4 papersME-CFS: 3 papersIRF7-metabolic: 3 paperspregnancy-fetal: 1 papersVDAC1: 1 papersmTOR-lysosomal: 1 papersISG15-mitophagy: 1 papersdNTPase: 1 papers