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Research blog

Every week, an automated pipeline sweeps PubMed, Europe PMC, Semantic Scholar, and bioRxiv for new work relevant to SAMHD1 p.A565T and its mechanism, scores each paper against this exact phenotype, and publishes the digest here. On the first of each month, a synthesis post summarizes what moved.

Posts are tagged by mechanistic pathway (cGAS-STING, NLRP3, VDAC1, ISG15-mitophagy, JAK-STAT, gene editing, and others) so you can follow a single thread through the literature — see the pathway map for what each tag means and how they connect. Subscribe via the RSS icon in the top bar.

How to read the scores

Each paper carries a 0–10 relevance score. 7–10 is high relevance (directly on-mechanism); 5–6 is adjacent; 3–4 is a possible specialty bridge worth a glance. Scores are generated by a language model against a fixed phenotype profile and are a triage aid, not a judgment of scientific quality.

SAMHD1 Research Digest — 2026-09-09

Generated by samhd1_monitor | Model: claude-sonnet-5

Summary: 13 papers evaluated | 1 high-relevance (≥7) | 6 medium (5–6) | 6 low (3–4) | 0 scored <3

🔴 High Relevance (Score 7–10)

Auto-added to Zotero (threshold ≥6)

Metabolic regulation of mitochondrial DNA (mtDNA) homeostasis. (from mitochondrial biology/metabolism)
Medeiros Tania Catarina; Calabrese Gaetano — Biochimica et biophysica acta. Molecular cell research 2026
Score: 7/10 | Pathways: POLG-mtDNA, mito-dNTP-transport, nucleotide-rewiring, dNTPase

This review directly addresses mitochondrial nucleotide pool regulation and POLG-driven mtDNA replication/quality control, mechanistically central to the PURPLE/GOLD streams of dGTP-driven mitochondrial dysfunction in SAMHD1 haploinsufficiency.
DOI: 10.1016/j.bbamcr.2026.120220

🟡 Medium Relevance (Score 5–6)

Score ≥6 auto-added to Zotero; lower scores: review manually

The Oxidative–Mitochondrial–Inflammatory Axis in Retinitis Pigmentosa: Extracellular mtDNA as Biomarker and Therapeutic Read-Out (from Ophthalmology (retinitis pigmentosa))
— Antioxidants 2026
Score: 6/10** | Pathways: cGAS-STING, NLRP3, POLG-mtDNA, treatment-target

This review details mtDNA release-driven cGAS-STING/TLR9/NLRP3 neuroinflammation via oxidative-mitochondrial dysfunction, directly paralleling the BLUE/PURPLE loops in SAMHD1 pathology though in a distinct retinal degeneration context.
DOI: 10.3390/antiox15091110

Understanding Dysfunctional Autophagy and Mitophagy in Inflammatory Cardiovascular Disease. (from Cardiology)
Michael E. Kaiser; Toni-ann Lewis; M. Malekan; Manish A. Parikh; Gioia Turitto — Cardiology in review 2026
Score: 6/10 | Pathways: NLRP3, mito-ROS-NF-kB, ISG15-mitophagy, clinical-phenotype

Details mitophagy/autophagy failure, mtDNA/DAMP release, and NLRP3-driven pyroptosis in cardiovascular inflammation, directly paralleling the mitochondrial-NLRP3-IL-1β mechanistic axis relevant to the SAMHD1 interferon-mitochondrial syndrome's cardiac phenotype risk.
DOI: 10.1097/crd.0000000000001302

Organelle-orchestrated cGAS-STING signaling and its role in neurodegeneration. (from Neurodegeneration/organelle biology)
Jin-Yue Liu; Sheng-ye Liu; Li-Xian Ran; Wenhao Qiao; Fan Zhang — Pharmacological research 2026
Score: 6/10 | Pathways: cGAS-STING, treatment-target

This review details organelle regulation of cGAS-STING (mitochondria, ER, MAMs, Golgi, lysosomes) and its role in chronic neuroinflammation, directly relevant to the BLUE loop mechanism (VDAC1/mtDNA/cGAS/STING/IFN-I) underlying the SAMHD1 A565T interferonopathy and its neurologic/AuDHD phenotypes, though it does not address SAMHD1 or NLRP3/NF-kB crosstalk directly.
DOI: 10.1016/j.phrs.2026.108216

Peroxiredoxin 6 limits mitochondrial peroxidation to prevent mitochondrial ER contact site assembly and inflammatory signalling following adaptive stress (from muscle physiology/redox biology)
PengLin Li; Yating Zheng; Jiwang Tang; Qin Xia; José C Casas-Martinez — bioRxiv 2026
Score: 6/10 | Pathways: VDAC1, NLRP3, mito-ROS-NF-kB, treatment-target

Demonstrates mitochondrial lipid peroxidation driving mtDNA release via MERCS/calcium dysregulation and innate immune activation, mechanistically paralleling the VDAC1-mtDNA-cGAS/NLRP3 axis central to SAMHD1 haploinsufficiency pathology even though SAMHD1 itself is not studied.
DOI: 10.64898/2026.07.24.740509

p300 Degradation by the p53-SIAH1 Axis Relieves TBK1 Acetylation to Enhance Innate Antiviral Immunity. (from virology/molecular oncology (p53-SIAH1-p300 axis in antiviral immunity))
Yu Huidi; Zhan Zhihao; Pan Xiaoxiang; Zhang Xinyue; Liu Penggang — Advanced science (Weinheim, Baden-Wurttemberg, Germany) 2026
Score: 6/10 | Pathways: cGAS-STING, NF-kB-IKK, treatment-target

Identifies p300-mediated TBK1 acetylation as a brake on IRF3-driven type I IFN production, directly relevant to the BLUE cGAS-STING-IRF3-IFN loop and NF-kB/IKK crosstalk central to the SAMHD1 interferonopathy model, though not SAMHD1-specific.
DOI: 10.1002/advs.76101

Next-Generation Genome Editing: Overcoming CRISPR-Cas9 Limitations with Prime Editing and PASTE Technology (from gene therapy/genome engineering)
Vikash Kumar; Aman Kumar; Balak Das Kurmi — Current Pharmacogenomics and Personalized Medicine 2026
Score: 5/10 | Pathways: prime-editing, gene-therapy-delivery

General review of prime editing and PASTE technology relevant as a future correction strategy for a heterozygous missense variant like SAMHD1 A565T, but does not address SAMHD1 or its mechanisms directly.
DOI: 10.2174/0118756921492763260804044215

🟢 Low Relevance (Score 3–4)

Potential specialty bridges — skim titles

Cell-Free Mitochondrial DNA as a Damage-Associated Molecular Pattern and Candidate Biomarker in Sickle Cell Disease Vaso-Occlusive Crisis: A Scoping Review (from Hematology (sickle cell disease))
Amoako Jerriod Paul Amoako; Owusu-Andoh Alexis; PSVV Charan; Atta-Poku Doris Ewu — 2026
Score: 4/10 | Pathways: cGAS-STING, VDAC1, clinical-phenotype

This scoping review discusses cf-mtDNA as a DAMP activating cGAS-STING-TBK1 in sickle cell vaso-occlusive crisis, mechanistically parallel to the BLUE loop but in a distinct disease with no SAMHD1 connection.
DOI: 10.21203/rs.3.rs-10864540/v1

ZBP1-mediated sensing of genomic stress in cancer therapy (from Oncology/cell death biology)
Xiao Zhong; Siddharth Balachandran; Ting Zhang — Ferroptosis and Oxidative Stress 2026
Score: 3/10 | Pathways: other

ZBP1/necroptosis/RIPK3 cancer-therapy pathway is a distinct innate nucleic-acid sensing axis with only tangential overlap (Z-RNA/R-loop stress) to SAMHD1's cGAS-STING/NLRP3/mitochondrial mechanisms, and no direct SAMHD1 or family-phenotype connection.
DOI: 10.70401/fos.2026.0035

Somatic Genome Editing in Cardiovascular Disease: Platforms, Targets, and Translational Progress (from cardiology/gene therapy)
Khawli George; Gorini Francesca; Palazzo Mariangela; Daher Jalil; Borghini Andre — preprint (preprint) 2026
Score: 3/10 | Pathways: prime-editing, gene-therapy-delivery

This is a general review of somatic genome-editing platforms for cardiovascular disease (liver PCSK9/ANGPTL3/TTR, myocardial MYH7/MYBPC3) with no connection to SAMHD1, interferon/inflammasome pathways, or myeloid/immune cell correction strategies relevant to A565T.
DOI: 10.20944/preprints202609.0314.v1

Cascade-catalytic microneedles convert the tumor cholesterol shield into an oxidative spear for self-amplifying ferroptosis-driven cancer immunotherapy. (from Oncology/nanomedicine biomaterials engineering)
Rongjie Yang; Yu Zhang; Yushu Dong; Shuiling Chen; Ming Li — Biomaterials 2026
Score: 3/10 | Pathways: cGAS-STING

This paper uses cGAS-STING activation as a downstream immunotherapy mechanism in cancer nanomedicine, but is unrelated to SAMHD1 biology, dNTP metabolism, or the interferon-mitochondrial syndrome described in the disease profile.
DOI: 10.1016/j.biomaterials.2026.124474

From immune dysregulation to renal injury: mechanistic insights and translational opportunities in immune-mediated nephropathies. (from Nephrology)
Xiaoming Wang — Frontiers in cell and developmental biology 2026
Score: 3/10 | Pathways: cGAS-STING, NLRP3, JAK-STAT, NF-kB-IKK, other

This nephrology review discusses cGAS-STING, NLRP3, NF-κB, and JAK-STAT pathways generically in immune-mediated kidney disease but has no direct connection to SAMHD1, its variants, or the documented family phenotypes.
DOI: 10.3389/fcell.2026.1878787

Single-Cell and Spatial Transcriptomics Define Eosinophil Heterogeneity during Influenza A Virus-induced Exacerbation of Fungal Allergic Asthma in C57BL/6 mice. (from pulmonology/immunology (allergic asthma and influenza))
Veltri Anthony J; Wells Anthony J; Baus Magdaline; Mathur Sameer K; Samarasinghe — Journal of leukocyte biology 2026
Score: 3/10 | Pathways: JAK-STAT, other

Samhd1 appears only as one of many interferon-stimulated genes noted in a mouse eosinophil single-cell transcriptomics study of flu/asthma, with no mechanistic or clinical link to SAMHD1 haploinsufficiency or the syndrome described.
DOI: 10.1093/jleuko/qiag120

Pathway Coverage This Week

  • cGAS-STING: 6 papers
  • NLRP3: 4 papers
  • treatment-target: 4 papers
  • other: 3 papers
  • POLG-mtDNA: 2 papers
  • mito-ROS-NF-kB: 2 papers
  • clinical-phenotype: 2 papers
  • VDAC1: 2 papers
  • NF-kB-IKK: 2 papers
  • prime-editing: 2 papers
  • gene-therapy-delivery: 2 papers
  • JAK-STAT: 2 papers
  • mito-dNTP-transport: 1 papers
  • nucleotide-rewiring: 1 papers
  • dNTPase: 1 papers
  • ISG15-mitophagy: 1 papers

SAMHD1 Research Digest — 2026-09-06

Generated by samhd1_monitor | Model: claude-sonnet-5

Summary: 13 papers evaluated | 2 high-relevance (≥7) | 6 medium (5–6) | 5 low (3–4) | 0 scored <3

🔴 High Relevance (Score 7–10)

Auto-added to Zotero (threshold ≥6)

The mitochondrial RNA extrusion-induced innate immunity is regulated by N6-methyladenosine machinery (from RNA epigenetics/molecular virology)
Hu Qing; Zhang Yifei; Wang Shixuan; Zeng Xueping; Wang Fengyu — preprint (preprint) 2026
Score: 7/10 | Pathways: VDAC1, cGAS-STING, NLRP3, treatment-target

This paper details VDAC1-mediated mitochondrial nucleic acid (mtRNA) extrusion activating cytosolic PRRs (RIG-I/MDA5/TLR/PKR), directly extending the BLUE-loop VDAC1-macropore mechanism central to SAMHD1 A565T interferon pathology beyond mtDNA to mtRNA, with m6A machinery as a novel druggable node.
DOI: 10.64898/2026.08.27.747681

Neonatal Aicardi-Goutières syndrome presenting with macrophage activation syndrome-like hyperinflammation and severe congenital glaucoma: a case report. (from pediatric rheumatology/neonatology and ophthalmology)
Konak Murat; Bozkurt Banu; Ceylaner Gülay; Cüceoğlu Müşerref Kasap; Özdemir Fati — Pediatric rheumatology online journal 2026
Score: 7/10 | Pathways: AGS-spectrum, JAK-STAT, treatment-target, clinical-phenotype

AGS type 2 case with type I interferonopathy responding to JAK1/2 inhibitor (ruxolitinib) directly parallels the SAMHD1 interferonopathy spectrum, MAS-like hyperinflammation, and glaucoma phenotype tracked in the family, plus congenital glaucoma overlaps with a listed family phenotype.
DOI: 10.1186/s12969-026-01264-x

🟡 Medium Relevance (Score 5–6)

Score ≥6 auto-added to Zotero; lower scores: review manually

Cardiomyocyte-intrinsic somatic mtDNA mutations induce an OXPHOS-dependent immune response and promote progressive heart failure. (from cardiology/aging biology)
Bubb Kristina; Rigoni Giovanni; Papadea Polyxeni; Pironti Gianluigi; Misic Jelen — Science advances 2026
Score: 6/10 | Pathways: POLG-mtDNA, mito-ROS-NF-kB, clinical-phenotype

Demonstrates that cardiomyocyte-intrinsic POLG-driven mtDNA mutations trigger an immune/antigen-presentation response and progressive heart failure, paralleling the PURPLE-stream POLG stalling→ox-mtDNA→immune activation mechanism and supporting cardiac relevance of mitochondrial-immune crosstalk in the SAMHD1 model.
DOI: 10.1126/sciadv.aec8606

Beyond genes: EpiSwitch® and Orion platform-powered 3D genome architecture biomarkers reveal shared biology across ME/CFS, long COVID, PTSD, rheumatoid arthritis, and multiple sclerosis. (from systems genomics/epigenetics (3D chromatin architecture biomarker platform) applied across rheumatology, neurology, and post-viral fatigue syndromes)
Hunter Ewan; Alshaker Heba; Vugrinec Dominik; Bautista Shekinah; Gebregzabhar Ab — Journal of translational medicine 2026
Score: 6/10 | Pathways: ME-CFS, cGAS-STING, mTOR-lysosomal, JAK-STAT, clinical-phenotype

This paper identifies shared immune/interferon/mitochondrial/mTOR pathway convergence across ME/CFS, long COVID, RA, and MS using 3D genomic architecture analysis, directly relevant to the proband's ME/CFS phenotype and the family's autoimmune/interferonopathy features (RA tracked in family phenotypes) even though SAMHD1 is not mentioned.
DOI: 10.1186/s12967-026-08874-9

Modulatory effects of methyl gallate on the inflammatory response in gout arthritis via P2X7 receptor. (from Pharmacology/Rheumatology)
Pereira Felipe M S; Correa Luana B; Seito Leonardo N; Ranke Natalia L VON; Mende — Anais da Academia Brasileira de Ciencias 2026
Score: 6/10 | Pathways: NLRP3, urate-NLRP3, treatment-target

This paper directly addresses the GOLD pathway (dGTP→purine catabolism→uric acid→MSU crystals→NLRP3) via P2X7-mediated MSU/NLRP3 activation and IL-1β release, offering a treatment target relevant to the gout phenotype tracked in the family.
DOI: 10.1590/0001-3765202620250722

Mitochondrial immunometabolism in sepsis: bridging immune cell dysfunction and organ failure. (from Critical care/sepsis immunometabolism)
Zhang Xingzhan; Zhao Ling; Fu Wei; Pan Lili; Wu Huanhuan — Frontiers in immunology 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, mito-ROS-NF-kB, treatment-target

Reviews mtDNA/mtROS/cardiolipin-driven cGAS-STING and NLRP3 activation as core drivers of sepsis organ failure, mechanistically overlapping with the SAMHD1 A565T ox-mtDNA→cGAS-STING/NLRP3 loops even though SAMHD1 itself is not mentioned.
DOI: 10.3389/fimmu.2026.1921226

Leptin attenuates heat stress-induced mitoxyperilysis in porcine Sertoli cells by suppressing the mtDNA-cGAS-STING axis. (from veterinary reproductive biology/animal science)
Guo Ming; Zhang Jinyang; Gu Shanshan; Gao Yawen; Zhu Zhendong — Journal of animal science and biotechnology 2026
Score: 6/10 | Pathways: cGAS-STING, VDAC1, NF-kB-IKK, mito-ROS-NF-kB, treatment-target

Demonstrates VDAC1-mediated mtDNA leakage activating cGAS-STING-TBK1-IRF3/NF-κB axis and inflammatory cytokine production, directly paralleling the BLUE pathway mechanism in the SAMHD1 model, with leptin as a novel mitochondrial-protective therapeutic modulator of this axis.
DOI: 10.1186/s40104-026-01489-6

Gut microbiota–mitochondria–barrier–multiorgan axis: a network-based hypothesis for systemic injury (from Gastroenterology/Critical Care Medicine)
Yachao Li; Huai-Jue Qiu; Xiang Gao; Yanling Zhang; Qin Xia — Frontiers in Immunology 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, mito-ROS-NF-kB, clinical-phenotype

Describes mtDNA/mtDAMP-driven cGAS-STING and NLRP3 activation as a mechanistic hub linking mitochondrial dysfunction to systemic inflammation, paralleling the SAMHD1-driven Loop A/B mitochondrial-innate immune convergence though in a gut-microbiota context rather than SAMHD1 pathway directly.
DOI: 10.3389/fimmu.2026.1885379

🟢 Low Relevance (Score 3–4)

Potential specialty bridges — skim titles

Quantitative adaptor heterogeneity sets single-cell thresholds for innate immune activation and attenuation (from single-cell biophysics/systems immunology)
Dey Arpan; Cui Yuhao; Nawalpuri Bharti; Meisl Georg; Sewell Gavin — preprint (preprint) 2026
Score: 4/10 | Pathways: NF-kB-IKK, other

This paper studies MyD88/TLR-driven NF-κB signaling heterogeneity in macrophages, tangential to the SAMHD1-cGAS-STING-NLRP3-NF-κB interferonopathy axis but not directly connected to SAMHD1, dNTP metabolism, or mitochondrial pathology.
DOI: 10.21203/rs.3.rs-10682444/v1

Mutant p53 Gain-of-Function and Immune Suppression: Mathematical Modeling of STING-TBK1-IRF3 Axis Restoration for Enhanced Cancer Therapy. (from computational oncology/mathematical biology)
Omer Salaheldin; Ouifki Rachid; Mambili-Mamboundou Hermane — Mathematical biosciences 2026
Score: 4/10 | Pathways: cGAS-STING

This is a mathematical modeling paper about mutant p53 suppression of the STING-TBK1-IRF3 axis in cancer immune evasion, touching the same IFN-I signaling node relevant to SAMHD1 biology but with no connection to SAMHD1, dNTP metabolism, or the family phenotype.
DOI: 10.1016/j.mbs.2026.109806

NLRP3 Inflammasome Activation and Atherogenic Lipid Profile in Hemodialysis Patients. (from Nephrology/dialysis)
Abdelaziz Mohammed N; Elshabrawy Nehal; Almenshawy Ahmed; Elsodany Karim A; Elka — Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 2026
Score: 3/10 | Pathways: NLRP3

Studies NLRP3 inflammasome and lipid atherogenicity in hemodialysis patients without any SAMHD1, interferon, or mitochondrial dNTP connection, only tangentially touching the NLRP3 node in this framework.
DOI: 10.1002/1744-9987.70158

Precision genome editing strategies for enduring lipid lowering in atherosclerosis. (from Cardiology/lipidology gene therapy)
Chowdhury Durlav; Singh Nirdesh; Garai Swarnalata; Pandey Devi Prasad; Bodakhe S — European journal of pharmacology 2026
Score: 3/10 | Pathways: prime-editing, gene-therapy-delivery

Reviews precision genome editing (CRISPR, base/prime editing, AAV/LNP delivery) for lipid-lowering in atherosclerosis, offering only generic technology overlap with gene therapy correction strategies but no SAMHD1, interferonopathy, or mitochondrial pathway relevance.
DOI: 10.1016/j.ejphar.2026.179312

NIR-II Small-Molecule Shuttle-Like Nanoassemblies for Mild-Temperature NIR-II Photothermal Enhanced Cuproptosis/STING Activation and Cancer Immunotherapy. (from oncology nanomedicine/photothermal therapy)
Dong Xue; Zhu Junfan; Sun Ying; Li Nianshu; Dai Shipeng — 2026
Score: 3/10 | Pathways: cGAS-STING, VDAC1

This is a cancer nanomedicine paper using mtDNA-release/cGAS-STING activation as an immunotherapy mechanism in tumors, unrelated to SAMHD1 haploinsufficiency but tangentially touching the same downstream cGAS-STING/mtDNA-release pathway.
DOI: 10.1002/smll.75620

Pathway Coverage This Week

  • cGAS-STING: 7 papers
  • NLRP3: 5 papers
  • treatment-target: 5 papers
  • clinical-phenotype: 4 papers
  • mito-ROS-NF-kB: 4 papers
  • VDAC1: 3 papers
  • JAK-STAT: 2 papers
  • NF-kB-IKK: 2 papers
  • AGS-spectrum: 1 papers
  • POLG-mtDNA: 1 papers
  • ME-CFS: 1 papers
  • mTOR-lysosomal: 1 papers
  • urate-NLRP3: 1 papers
  • other: 1 papers
  • prime-editing: 1 papers
  • gene-therapy-delivery: 1 papers

SAMHD1 Research Digest — 2026-09-02

Generated by samhd1_monitor | Model: claude-sonnet-5

Summary: 8 papers evaluated | 2 high-relevance (≥7) | 4 medium (5–6) | 2 low (3–4) | 0 scored <3

🔴 High Relevance (Score 7–10)

Auto-added to Zotero (threshold ≥6)

Reprogramming Autoimmune Immunity via Mitochondrial Quality Control: Mechanisms, Biomarkers, and Windows for Intervention. (from Rheumatology/Autoimmunity)
Chen Xiao; Ding Jie; Meng Liu-Qing; Li Shu-Fang; Chen Yong — International immunopharmacology 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, ISG15-mitophagy, treatment-target, NF-kB-NLRP3-priming

This review directly discusses mitophagy/mtDNA-driven cGAS-STING-IFN-I amplification and NLRP3 hyperactivation as autoimmune drivers, mirroring the SAMHD1 A565T mitochondrial-interferon mechanism and proposing biomarker/treatment windows analogous to JAK inhibitor or MCC950-style interventions relevant to this family's phenotype.
DOI: 10.1016/j.intimp.2026.117316

Adipose-cartilage communication via EV-Mito-mtDNA signaling promotes osteoarthritis progression. (from Orthopedics/Rheumatology (osteoarthritis and obesity-adipose biology))
Gu Cheng; Liao Fawei; Kong Ganggang; Yin Shiyi; Jiang Yifei — 2026
Score: 7/10 | Pathways: cGAS-STING, mito-ROS-NF-kB, treatment-target

Demonstrates mtDNA (via EV transfer) activating cGAS-STING to drive inflammation and senescence, directly paralleling the BLUE loop (VDAC1-mtDNA-cGAS-STING-IFN) mechanism central to the SAMHD1 model, with therapeutic inhibition data.
DOI: 10.1126/sciadv.aee6780

🟡 Medium Relevance (Score 5–6)

Score ≥6 auto-added to Zotero; lower scores: review manually

Combined MEK1/2 and Autophagy Inhibition Suppresses Tumor Growth via STING-Mediated Type I Interferon Response in iCCA. (from Oncology (hepatobiliary cancer/MEK inhibitor pharmacology))
Sun Chengqiang; Gao Zheng; Dong Enfu; Ding Liangxia; Feng Shanru — Cancer science 2026
Score: 6/10 | Pathways: cGAS-STING, mTOR-lysosomal, ISG15-mitophagy, treatment-target

Demonstrates that autophagy/mitophagy suppresses cGAS-STING-TBK1 type I IFN signaling and that combined inhibition unleashes IFN-I output, directly modeling the mitophagy-IFN crosstalk (BLUE/RED loops) central to SAMHD1 pathology, though in an oncology (iCCA) rather than SAMHD1 context.
DOI: 10.1111/cas.70436

Neonatal Reversible Aortic Constriction Mice Model Unlocks Distinctive Footprints of Young Heart Recovery. (from Pediatric cardiology/cardiac surgery)
Huang Longming; Luo Kai; Zhang Xinjie; Zeng Guowei; Chen Bo — 2026
Score: 6/10 | Pathways: cGAS-STING, ISG15-mitophagy, treatment-target

This paper demonstrates the mtDNA-cGAS-STING pathway driving cardiac remodeling and shows mitophagy/urolithin A suppress STING activation, mechanistically paralleling the BLUE/RED loops in the SAMHD1 model and offering relevance to the cardiomyopathy/mitochondrial-cardiac phenotype tracked in the family, though it lacks any SAMHD1 connection.
DOI: 10.1161/jaha.125.047618

Uracil-DNA glycosylase 1 mitigates acute kidney injury inflammation by maintaining mtDNA homeostasis (from Nephrology)
xiaohui Liao; Wang Chunxia; Tang Wei; Xie Pan; Wang Yuting — 2026
Score: 6/10 | Pathways: cGAS-STING, POLG-mtDNA, NF-kB-NLRP3-priming

Demonstrates mtDNA damage/leakage driving cGAS-STING inflammatory signaling in acute kidney injury via UNG1/SSBP1-mediated mtDNA repair, mechanistically parallel to the POLG-stalling/ox-mtDNA/cGAS-STING loop central to SAMHD1 A565T pathology though in a distinct disease context.
DOI: 10.21203/rs.3.rs-10469724/v1

Single-cell Unperturbed Activation Profiling by mass cytometry captures in vivo immune signaling in SLE. (from Rheumatology/single-cell mass cytometry biomarker methodology)
Burns Marie; Ostendorf Lennard; Abbas Amro; Ferrara Sebastian; Hirseland Heike — Frontiers in immunology 2026
Score: 5/10 | Pathways: JAK-STAT, treatment-target, clinical-phenotype

SLE study demonstrating type I IFN-driven pSTAT1/pSTAT3 signaling and baricitinib (JAK inhibitor) treatment monitoring is mechanistically relevant to the RED IFN-JAK-STAT pathway and JAK inhibitor therapeutics in the SAMHD1 interferonopathy model, though it does not involve SAMHD1 directly.
DOI: 10.3389/fimmu.2026.1844288

🟢 Low Relevance (Score 3–4)

Potential specialty bridges — skim titles

Leukotrichia: A comprehensive review of follicular depigmentation. (from Dermatology)
Iamsumang Wimolsiri; Kositkuljorn Chaninan; Leerunyakul Kanchana; Sakpuwadol Naw — The Journal of international medical research 2026
Score: 4/10 | Pathways: poliosis-neural-crest, clinical-phenotype

This dermatology review on leukotrichia/piebaldism/Waardenburg-associated follicular depigmentation is tangentially relevant only insofar as it illuminates neural crest melanocyte biology underlying the family's tracked poliosis/silver-streak phenotype, with no direct SAMHD1 or interferon-mitochondrial pathway content.
DOI: 10.1177/03000605261483177

ZBP1 in Neuroinflammation and Neurodegeneration: Z-Nucleic-Acid Sensing, RHIM Signalling and Therapeutic Targeting. (from neurology/neuroimmunology)
Șerban Matei; Toader Corneliu; Covache-Busuioc Răzvan-Adrian — 2026
Score: 4/10 | Pathways: cGAS-STING, clinical-phenotype

ZBP1 senses oxidized mtDNA and self nucleic acids to trigger RIPK/MLKL inflammatory pathways in neuroinflammation, an innate-immune sensing mechanism parallel to but distinct from SAMHD1/cGAS-STING axis with only indirect relevance to the AuDHD/ME-CFS neuroinflammatory phenotype.
DOI: 10.3390/ijms27167478

Pathway Coverage This Week

  • cGAS-STING: 6 papers
  • treatment-target: 5 papers
  • ISG15-mitophagy: 3 papers
  • clinical-phenotype: 3 papers
  • NF-kB-NLRP3-priming: 2 papers
  • NLRP3: 1 papers
  • mito-ROS-NF-kB: 1 papers
  • mTOR-lysosomal: 1 papers
  • POLG-mtDNA: 1 papers
  • JAK-STAT: 1 papers
  • poliosis-neural-crest: 1 papers

Iterative genetic testing identifies SAMHD1 deficiency caused by a homozygous balanced translocation

The finding

This case report describes a patient with clinical features overlapping familial chilblain lupus—perniosis, acral autoamputation, small joint arthritis—alongside a type I interferon transcriptomic signature. Using a stepwise combination of exome sequencing, transcriptomics, and long-read genome sequencing, the authors identified a homozygous, balanced, reciprocal translocation disrupting the SAMHD1 locus (chr20q11.23) and joining it to chr17p11.2, with RNA-seq showing transcript coverage limited to SAMHD1's first four exons. This is reported as the first inborn error of immunity attributed to a homozygous balanced translocation.

Where it fits

This paper is a complete loss-of-function case, not a partial one — structurally, it sits far upstream of the SAMHD1 p.A565T model. Where A565T leaves ~40-60% residual dNTPase activity and produces a graded, "smouldering" phenotype, this translocation truncates the transcript after exon 4, effectively eliminating SAMHD1 protein output. The clinical consequence — a strong type I IFN signature — is consistent with unrestrained flux through the root-cause pathway feeding Loop A: loss of SAMHD1 control over dNTP pools and mitochondrial DNA release, driving cGAS–STING–IRF3 signaling and downstream ISG induction. It's a useful boundary case: it shows what happens at the far end of the SAMHD1-dosage spectrum from the heterozygous, partial-function A565T model this project studies, reinforcing the idea that SAMHD1 sits on a dosage continuum from asymptomatic heterozygosity to classical Aicardi-Goutières-like presentations.

Caveats

  • This is a complete biallelic loss-of-function (homozygous translocation truncating the gene), fundamentally different from the heterozygous, partial-activity A565T variant this project models — mechanisms and severity should not be extrapolated directly.
  • Single case report: no functional dNTPase assays, no mitochondrial/inflammasome readouts, and no data on NLRP3 or IL-18 axis involvement — the paper documents an IFN signature by transcriptomics only, not pathway mechanism.
  • Co-occurring pathogenic MN1 variant complicates phenotype attribution; the authors themselves separate MN1-driven features (microcephaly, hearing loss) from the SAMHD1-attributable immune phenotype, but overlap/confounding in a single patient can't be fully excluded.

What to watch

Whether functional follow-up (e.g., IFN signature reversal with JAK inhibition, or dNTP pool measurement) is pursued in this patient, and whether this translocation mechanism is found in other undiagnosed interferonopathy cases where standard exome sequencing missed structural variants entirely.

Source: Iterative genetic testing identifies SAMHD1 deficiency caused by a homozygous balanced translocation. — Journal of human immunity 2026.

SAMHD1 Research Digest — 2026-08-30

Generated by samhd1_monitor | Model: claude-sonnet-5

Summary: 22 papers evaluated | 3 high-relevance (≥7) | 7 medium (5–6) | 12 low (3–4) | 0 scored <3

⚠️ Partial run: preprint returned no papers (likely rate-limited). Coverage this week is incomplete; the missed papers are not marked seen and will be picked up on the next run.

🔴 High Relevance (Score 7–10)

Auto-added to Zotero (threshold ≥6)

Iterative genetic testing identifies SAMHD1 deficiency caused by a homozygous balanced translocation. (from Clinical genetics/genomics (structural variant diagnostics))
Baker Paul J; Zhang Yaoyuan; Bishop Imogen; Cleveland Madeline L; McAllan Alexan — Journal of human immunity 2026
Score: 9/10 | Pathways: cGAS-STING, JAK-STAT, AGS-spectrum, dNTPase, clinical-phenotype

Directly demonstrates SAMHD1 loss-of-function via a novel structural variant (balanced translocation) causing type I interferon signature and familial chilblain lupus, reinforcing the core SAMHD1-interferonopathy mechanism relevant to the A565T haploinsufficiency model.
DOI: 10.70962/jhi.20260044

Mitophagy mitigates mitochondrial DNA-induced activation of cGAS-STING in autoimmune thyroiditis (from Endocrinology (autoimmune thyroiditis))
Xiao-Chen Xie; Yang Guo; Ran Guo; Yongze Li; Shan-Shan Wang — Nature Communications 2026
Score: 8/10 | Pathways: cGAS-STING, ISG15-mitophagy, NF-kB-IKK, treatment-target, clinical-phenotype

Demonstrates that mitophagy failure (PINK1/Parkin/TAX1BP1 axis, mechanistically parallel to ISG15-mediated mitophagy block in the RED stream) causes mtDNA leakage and cGAS-STING-driven autoimmune inflammation, directly reinforcing the BLUE/RED loop mechanism and validating STING inhibition (C176) as a therapeutic strategy relevant to the SAMHD1 interferonopathy model.
DOI: 10.1038/s41467-026-76047-9

APOE4-AGE axis is linked to mtDNA release and cGAS-STING mediated neuroinflammation in the aging brain. (from Neurodegeneration/Alzheimer's disease research)
Akhter Firoz; Akhter Asma; Zhou Jasmine; Xi Michelle; Zhu Donghui — Free radical biology & medicine 2026
Score: 7/10 | Pathways: cGAS-STING, mito-ROS-NF-kB, clinical-phenotype

Demonstrates mtDNA release triggering cGAS-STING-TBK1-IRF3-driven type I interferon and neuroinflammation via mitochondrial dysfunction, directly paralleling the BLUE loop mechanism (VDAC1/mtDNA/cGAS/STING/IFN-I) central to the SAMHD1 syndrome, though in an APOE4/AGE-RAGE rather than SAMHD1 context.
DOI: 10.1016/j.freeradbiomed.2026.08.054

🟡 Medium Relevance (Score 5–6)

Score ≥6 auto-added to Zotero; lower scores: review manually

Mitochondrial immunometabolism in sepsis: bridging immune cell dysfunction and organ failure (from Critical care/sepsis immunometabolism)
Xingzhan Zhang; Ling Zhao; Wei Fu; Lili Pan; Huanhuan Wu — Frontiers in Immunology 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, mito-ROS-NF-kB, treatment-target

Reviews mitochondrial mtDNA/mtROS-driven cGAS-STING and NLRP3 activation and its crosstalk with NF-kB in immune cells, mechanistically overlapping with the BLUE/PURPLE/GOLD loops in the SAMHD1 model even though sepsis rather than SAMHD1 haploinsufficiency is the trigger.
DOI: 10.3389/fimmu.2026.1921226

Interferon Regulatory Factors as Potential Therapeutic Targets in Cardiovascular Disease: Focusing on Vascular Inflammation (from Cardiology/vascular biology)
Chen-Xi Bai; Wei-Xu Liu; Yu-Bo Wang; Hui-Xia Zhu; Xing Fan — International Journal of Molecular Sciences 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, JAK-STAT, NF-kB-IKK, treatment-target

Reviews IRF1/3/5/7 pro-inflammatory signaling via cGAS-STING/NLRP3/NF-kB/JAK-STAT in vascular disease, mechanistically parallel to the IFN-I/NLRP3 axis in SAMHD1 A565T interferonopathy but without direct SAMHD1 or mitochondrial dNTP linkage, and offers cardiovascular relevance given the family's cardiac/vascular phenotype risk.
DOI: 10.3390/ijms27177647

p21 (CDKN1A) Is the Major Driver of Sulforaphane-Mediated Reduction in SAMHD1 T592 Phosphorylation in Macrophages. (from virology/pharmacology (HIV restriction and nutraceutical NRF2 signaling))
Marcelino Bianka Nicolle Pena; Girard Kiersten; Letourneau Lauren; Lewin Andrew; — Biomolecules 2026
Score: 6/10 | Pathways: dNTPase, treatment-target, other

Demonstrates regulation of SAMHD1 phosphorylation (T592) via p21/CDK in macrophages and its role in antiviral restriction, relevant to SAMHD1 functional regulation though not the A565T dNTPase catalytic mechanism directly.
DOI: 10.3390/biom16081213

Investigating the Role of Type I Interferon Signaling on Muscle Disease Using Mouse Models. (from Rheumatology/Muscle disease (myositis))
Spathis Rita; Narvesen Sabrina; Robles Kuriplach Deeva; Huang Karen; Sundar Teja — Arthritis & rheumatology (Hoboken, N.J.) 2026
Score: 6/10 | Pathways: JAK-STAT, treatment-target, clinical-phenotype

Demonstrates JAK inhibitor (tofacitinib) suppression of type I IFN signature and improved survival in murine myositis models driven by IFN-beta overexpression, directly supporting JAK-STAT as a therapeutic target relevant to the SAMHD1 interferonopathy mechanism though not SAMHD1-specific.
DOI: 10.1002/art.70096

Development of mitochondrial mutator pigs exhibiting increased mitochondrial DNA mutations and premature aging via prime editing. (from Comparative/translational aging biology using large-animal (porcine) prime-editing models)
Chen Fangbing; Liang Yanhui; Zheng Wei; Yao Aobo; Wang Ning — Science advances 2026
Score: 5/10 | Pathways: POLG-mtDNA, prime-editing, gene-therapy-delivery

Demonstrates POLG proofreading-deficiency-driven mtDNA mutation accumulation and premature aging using prime editing in a large animal model, directly relevant to the PURPLE-stream POLG stalling node and to prime-editing technology tracked for future SAMHD1 correction, though not immune-cell or SAMHD1-specific.
DOI: 10.1126/sciadv.adu0632

Alcohol intake reprograms hepatic immune-metabolic circuits to exacerbate murine atherosclerosis and human cardiovascular risk. (from Hepatology/Cardiology)
Hoebinger Constanze; Semmler Georg; Petrenko Oleksandr; Rajcic Dragana; Hoffelne — JHEP reports : innovation in hepatology 2026
Score: 5/10 | Pathways: urate-NLRP3, NLRP3, clinical-phenotype

Demonstrates hyperuricemia-driven hepatic NLRP3 upregulation and inflammasome activation linked to dyslipidemia and cardiovascular risk, paralleling the GOLD pathway (dGTP→purine catabolism→uric acid→NLRP3) in the SAMHD1 model though not SAMHD1-specific.
DOI: 10.1016/j.jhepr.2026.101932

Understanding cardiovascular aging as a disorder of mitochondrial network (from Cardiology/cardiovascular aging)
Taslima Akter Shila; Dhrubo Ahmad; Jianli Zhao; Huilan Tan; Bo Wang — The journal of cardiovascular aging 2026
Score: 5/10 | Pathways: cGAS-STING, mito-ROS-NF-kB, clinical-phenotype

This review discusses mitochondrial DNA/vesicle release activating cGAS-STING and driving sterile inflammation in cardiovascular aging, which parallels the SAMHD1-driven mitochondrial-interferon mechanism but lacks direct SAMHD1 or NLRP3/inflammasome linkage and focuses on aging rather than the specific disease pathway.
DOI: 10.20517/jca.2026.07

🟢 Low Relevance (Score 3–4)

Potential specialty bridges — skim titles

From mechanical adaptation to innate immune reprogramming in osteoarthritis: a load-immunity framework (from Orthopedics/Rheumatology (mechanobiology of osteoarthritis))
Shiguo Zuo; Lijun He; Z. Hou; Quanliang Tian; Yilong Yang — Frontiers in Immunology 2026
Score: 4/10 | Pathways: cGAS-STING, NLRP3, mito-ROS-NF-kB

Discusses cGAS-STING and NLRP3 mitochondrial danger-signal pathways shared with the SAMHD1 mechanism but in an osteoarthritis mechanical-loading context unrelated to SAMHD1 dysfunction or the family phenotype spectrum.
DOI: 10.3389/fimmu.2026.1931112

Post-translational control of MAVS signaling: linking mitochondrial antiviral immunity to metabolic and cellular stress contexts (from Mitochondrial biochemistry/virology (PTM signaling biology))
Nao Morimoto; Tomohiko Okazaki — Frontiers in Physiology 2026
Score: 4/10 | Pathways: cGAS-STING, VDAC1, other

This paper details PTM regulation of MAVS, a mitochondrial RLR adaptor producing type I IFN, offering a conceptually parallel but mechanistically distinct pathway to the SAMHD1-VDAC1-cGAS-STING axis without direct SAMHD1 or NLRP3/ISG15 involvement.
DOI: 10.3389/fphys.2026.1907325

Advances in prime editing: Molecular innovations, Large-fragment engineering, and AI-driven design. (from genome engineering/synthetic biology)
Muhammad Waqar; Cao Xi; Umar Aziz; Nauman Khan; Jiao Ziao — Biodesign research 2026
Score: 4/10 | Pathways: prime-editing, gene-therapy-delivery

General review of prime editing technology advances with no immune/myeloid-specific application or SAMHD1 correction focus, offering only background relevance to future gene therapy translation.
DOI: 10.1016/j.bidere.2026.100104

The Role of Skeletal Muscle Mitochondria in NLRP3 Inflammasome Signaling. (from exercise physiology/skeletal muscle biology)
Sangha Jada; Hood David A — Biomolecules 2026
Score: 4/10 | Pathways: NLRP3, mito-ROS-NF-kB

Reviews mitochondrial DAMP-driven NLRP3 activation and exercise mitigation in skeletal muscle, relevant to the mitochondrial-inflammasome mechanism but lacks SAMHD1, interferon, or clinical-phenotype connections central to this disease profile.
DOI: 10.3390/biom16081218

Glyphosate induces intestinal inflammatory injury associated with mitochondrial-lysosomal dysfunction, cGAS-STING activation, and pyroptosis-related responses in common carp (Cyprinus carpio L.). (from aquatic toxicology/veterinary environmental science)
Zhang Shuyue; Ji Xiaofeng; Zhong Haoyu; Wang Zehui; Li Xiaohui — Fish & shellfish immunology 2026
Score: 4/10 | Pathways: cGAS-STING, NLRP3, mito-ROS-NF-kB

This fish toxicology study demonstrates mtDNA release-cGAS-STING-NLRP3-pyroptosis signaling analogous to Loop A/B mechanisms in the SAMHD1 model, but is a non-mammalian xenobiotic toxicity paper without direct genetic or clinical relevance to SAMHD1 haploinsufficiency.
DOI: 10.1016/j.fsi.2026.111682

Non-invasive Ultra-early in Utero Detection and Precision CRISPR-mediated Correction of Monogenic Embryonic Mutations: A Critical Appraisal of a Hypothetical Therapeutic Framework (from Prenatal diagnostics / gene therapy delivery)
S. Bittmann; E. Luchter; E. Moschüring-Alieva — Asian Journal of Medicine and Health 2026
Score: 3/10 | Pathways: prime-editing, gene-therapy-delivery, pregnancy-fetal

This is a general critical review of in utero cfDNA detection and CRISPR/prime-editing correction for monogenic disease, not specific to SAMHD1 or its core inflammatory pathways, but tangentially relevant as background for future gene-correction strategies applicable to a heterozygous missense variant like A565T.
DOI: 10.9734/ajmah/2026/v24i91427

From immune dysregulation to renal injury: mechanistic insights and translational opportunities in immune-mediated nephropathies (from Nephrology/Rheumatology)
Xiaoming Wang — Frontiers in Cell and Developmental Biology 2026
Score: 3/10 | Pathways: NLRP3, cGAS-STING, JAK-STAT, NF-kB-IKK

This is a general nephrology review of immune-mediated kidney diseases touching on shared innate-immune pathways (NLRP3, cGAS-STING, NF-kB, JAK-STAT) that overlap thematically with the SAMHD1 interferon-mitochondrial mechanism but has no direct SAMHD1, mitochondrial dNTP, or ME/CFS/family phenotype connection.
DOI: 10.3389/fcell.2026.1878787

A PepFect14 analog improves non-viral CRISPR delivery in primary human cells to facilitate genome editing and repair. (from Dermatology/gene therapy bioengineering)
A. du Rand; Courtney Masterson; Daniel J Verdon; Andrew Siow; E. Loef — Bioengineering & translational medicine 2026
Score: 3/10 | Pathways: gene-therapy-delivery

This paper describes a non-viral CRISPR delivery peptide for skin cell genome editing in epidermolysis bullosa, which is a gene-editing delivery advance but not targeted at myeloid/immune cells or SAMHD1 correction and thus only tangentially related.
DOI: 10.1002/btm2.70172

Delivering the blueprint: Advances and challenges in mRNA therapeutics for the respiratory system (from pulmonology/pharmaceutics)
Fangru Jia; Linlin Ma; Yanan Li — International Journal of Pharmaceutics: X 2026
Score: 3/10 | Pathways: gene-therapy-delivery

This review covers mRNA-LNP delivery to lung tissue generally, with only tangential relevance to SAMHD1 gene therapy since it doesn't address myeloid/HSC editing or immune cell delivery specific to the disease model.
DOI: 10.1016/j.ijpx.2026.100634

Neurotensin receptor agonist PD149163 modulates LPS-induced sub-acute gut inflammation by inhibiting TLR4/NF-κB/NLRP3 inflammasome pathway: In vivo, in silico and network pharmacology analyses. (from Gastroenterology/pharmacology)
Singh Priya; Mohanty Banalata — International immunopharmacology 2026
Score: 3/10 | Pathways: NLRP3, NF-kB-IKK

This paper studies TLR4/NF-κB/NLRP3 inhibition by a neurotensin receptor agonist in LPS-induced gut inflammation in mice, sharing pathway components with the SAMHD1 model but with no connection to SAMHD1, interferonopathy, or mitochondrial dNTP mechanisms.
DOI: 10.1016/j.intimp.2026.117321

Pain and Analgesic Doses Versus Free Interleukin 18 (IL-18F) Blood Levels Following Surgery: A Prospective Randomized Study of Patients With Minilaparotomy Cholecystectomy Versus Laparoscopic Cholecystectomy. (from Surgery/pain medicine)
Eskelinen Matti; Kuosmanen Viivi; Selander Tuomas; Kaarniranta Kai; Saimanen Iin — In vivo (Athens, Greece) 2026
Score: 3/10 | Pathways: NLRP3, clinical-phenotype

This paper studies IL-18/IL-18BP as postoperative pain biomarkers after cholecystectomy, touching the NLRP3-IL-18 axis and the family's cholecystectomy clustering phenotype but without any SAMHD1, interferon, or mitochondrial mechanism linkage.
DOI: 10.21873/invivo.14435

Generation of two homozygous iPSC lines carrying variants of uncertain significance in LMNA associated with cardiomyopathy. (from Cardiology/stem cell genetics)
Liu Lu; Wu David; Manhas Amit; Noishiki Chikage; Tripathi Dipti — Stem cell research 2026
Score: 3/10 | Pathways: prime-editing

This paper demonstrates prime editing to generate LMNA VUS iPSC lines for cardiomyopathy research, technically relevant to gene correction methodology but unrelated to SAMHD1 or its associated pathways.
DOI: 10.1016/j.scr.2026.104086

Pathway Coverage This Week

  • cGAS-STING: 10 papers
  • NLRP3: 9 papers
  • clinical-phenotype: 7 papers
  • mito-ROS-NF-kB: 6 papers
  • treatment-target: 5 papers
  • gene-therapy-delivery: 5 papers
  • JAK-STAT: 4 papers
  • NF-kB-IKK: 4 papers
  • prime-editing: 4 papers
  • dNTPase: 2 papers
  • other: 2 papers
  • AGS-spectrum: 1 papers
  • ISG15-mitophagy: 1 papers
  • POLG-mtDNA: 1 papers
  • urate-NLRP3: 1 papers
  • VDAC1: 1 papers
  • pregnancy-fetal: 1 papers

SAMHD1 Research Digest — 2026-08-26

Generated by samhd1_monitor | Model: claude-sonnet-5

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

🟡 Medium Relevance (Score 5–6)

Score ≥6 auto-added to Zotero; lower scores: review manually

Emerging microbiome-mitochondria crosstalk in host defense and infectious diseases: mechanistic insights into NLRP3 inflammasome activation and mtDNA-mediated immunomodulation. (from Gastroenterology/microbiome-infectious disease)
Lu Xinxing; Sun Wenbin; Zhang Daowei; Hou Bin; Tai Huiyu — Frontiers in cellular and infection microbiology 2026
Score: 6/10 | Pathways: NLRP3, cGAS-STING, mito-ROS-NF-kB, treatment-target

Reviews gut-microbiome-mtDNA-NLRP3/cGAS-STING crosstalk mechanistically parallel to the ox-mtDNA/NLRP3 and mitophagy pathways central to the SAMHD1 interferon-mitochondrial model, though not SAMHD1-specific.
DOI: 10.3389/fcimb.2026.1866924

Dysregulation of the KLF9/TXNRD2 Axis Leads to Mitochondrial DNA Oxidation and NLRP3 Inflammasome Activation in Ulcerative Colitis. (from gastroenterology)
Fan Yijia; Dai Lingling; Zhu Feng; Ping Mingfang; Zhu Xiaofeng — Journal of biochemical and molecular toxicology 2026
Score: 6/10 | Pathways: NLRP3, POLG-mtDNA, clinical-phenotype

Demonstrates ox-mtDNA release triggering NLRP3 inflammasome activation via a KLF9/TXNRD2 oxidative stress axis, mechanistically parallel to the PURPLE/GOLD ox-mtDNA-NLRP3 pathway though in a UC epithelial context rather than SAMHD1-driven interferonopathy.
DOI: 10.1002/jbt.71074

Dihydroquercetin alleviates mitochondrial dysfunction and inhibits NLRP3-mediated pyroptosis in primary hepatocytes from chronic liver failure patients. (from Hepatology/pharmacology)
Ao Shen; Pengxiang Wang; Bing Wu; Hong Fu; Yuqiao Zeng — American journal of translational research 2026
Score: 6/10 | Pathways: NLRP3, treatment-target, mito-ROS-NF-kB

Demonstrates NLRP3/caspase-1/IL-1β pyroptotic axis driven by mitochondrial dysfunction (ox-mtDNA release, JC-1 depolarization) in hepatocytes, directly paralleling the family's PURPLE/GOLD loop mechanism and hepatic steatosis phenotype, with a candidate therapeutic (DHQ) targeting the same NLRP3-mitochondrial node.
DOI: 10.62347/ifrp1860

The private truncating Toll-like receptor 7 p.Glu834* variant associates with juvenile-onset systemic lupus erythematosus and pathological cytokine expression in vitro. (from Rheumatology/pediatric lupus genetics)
Y. Renaudineau; J. Hawkes; Katarzyna Mizgalska; V. Natoli; J. Roachdown — Annals of the rheumatic diseases 2026
Score: 5/10 | Pathways: JAK-STAT, AGS-spectrum, clinical-phenotype, treatment-target

Describes a distinct monogenic type I interferonopathy (TLR7 gain-of-function) causing lupus via enhanced IFN signaling, mechanistically analogous but not directly linked to the SAMHD1-driven interferon-mitochondrial axis.
DOI: 10.1016/j.ard.2026.07.024

Pathway Coverage This Week

  • NLRP3: 3 papers
  • treatment-target: 3 papers
  • mito-ROS-NF-kB: 2 papers
  • clinical-phenotype: 2 papers
  • cGAS-STING: 1 papers
  • POLG-mtDNA: 1 papers
  • JAK-STAT: 1 papers
  • AGS-spectrum: 1 papers

SAMHD1 Research Digest — 2026-08-23

Generated by samhd1_monitor | Model: claude-sonnet-5

Summary: 16 papers evaluated | 1 high-relevance (≥7) | 6 medium (5–6) | 9 low (3–4) | 0 scored <3

🔴 High Relevance (Score 7–10)

Auto-added to Zotero (threshold ≥6)

Targeting mPTP with NIM811 Alleviates Pancreatic Injury and Inflammatory Response in Severe Acute Pancreatitis (from Gastroenterology/Critical Care (acute pancreatitis))
Feng Dan; Zhang Jia-Rui; Bai Xue; Chen Xia — 2026
Score: 7/10 | Pathways: cGAS-STING, VDAC1, treatment-target, other

Demonstrates mPTP/VDAC-adjacent mitochondrial membrane permeability leading to mtDNA release and cGAS-STING-driven inflammatory cytokine production (IL-1β, IL-6, TNF-α) in a mitochondrial damage model, directly paralleling the BLUE loop mechanism (mtDNA escape → cGAS/STING → IFN-inflammatory output) though in a distinct disease context (pancreatitis) without SAMHD1 involvement.
DOI: 10.21203/rs.3.rs-10616969/v1

🟡 Medium Relevance (Score 5–6)

Score ≥6 auto-added to Zotero; lower scores: review manually

The dual role of the cGAS-STING signaling pathway in kidney diseases: from acute injury to chronic fibrosis – molecular mechanisms and precision therapeutic strategies (from Nephrology)
Guangdong Qi; Fei Xue; Hualin Sun; Xinlei Yao; Qingyuan Liu — Frontiers in Pharmacology 2026
Score: 6/10 | Pathways: cGAS-STING, NF-kB-IKK, treatment-target

Reviews cGAS-STING mechanisms (mtDNA leakage, TBK1-IRF3/NF-kB, inflammation-fibrosis) and inhibitor strategies directly relevant to the BLUE loop pathway, though applied to renal disease rather than SAMHD1 context.
DOI: 10.3389/fphar.2026.1882994

Quercetin induces molecular hallmarks of immunogenic cell death and cGAS-STING pathway activation via mitochondrial DNA release in hepatocellular carcinoma cells. (from Oncology/pharmacology)
Lin Tong; Chen Yifan; Huang Zhengrong — Naunyn-Schmiedeberg's archives of pharmacology 2026
Score: 6/10 | Pathways: cGAS-STING, NF-kB-IKK, treatment-target

Demonstrates mtDNA release triggering cGAS-STING-TBK1-IRF3/p65 activation, directly modeling the core Loop A/NF-kB crosstalk mechanism though in an oncology drug-induction context rather than SAMHD1 dysfunction.
DOI: 10.1007/s00210-026-05815-7

Expanding the therapeutic landscape of Still's disease: the emerging role of JAK inhibitors. (from Rheumatology)
Ruscitti Piero; Ursini Francesco; Giacomelli Roberto; Cantarini Luca; Caso Franc — Expert opinion on pharmacotherapy 2026
Score: 6/10 | Pathways: JAK-STAT, NLRP3, treatment-target, clinical-phenotype

Reviews JAK inhibitors modulating IL-1/IL-6/IFN-γ and inflammasome-dependent pathways in Still's disease, directly relevant to the JAK-STAT and NLRP3 nodes and to JAKi therapeutic strategies applicable to the interferon-mitochondrial syndrome, though not SAMHD1-specific.
DOI: 10.1080/14656566.2026.2723582

Mitochondrial DNA in necrosis-like cell death in failing hearts: evidence and mechanisms fostering damage. (from cardiology)
Marciníková Andrea; Jarabicová Izabela; Horváth Csaba; Adameova Adriana — American journal of physiology. Cell physiology 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, treatment-target, other

This cardiology-focused review details mtDNA release triggering cGAS-STING and NLRP3/AIM2 inflammasome pathways driving necroptosis/pyroptosis in heart failure, mechanistically overlapping with the BLUE loop (VDAC1/mtDNA/cGAS-STING) and NLRP3 activation streams central to the SAMHD1 disease model, though it does not address SAMHD1 or dNTPase biology directly.
DOI: 10.1152/ajpcell.00266.2026

The Role of Skeletal Muscle Mitochondria in NRLRP3 Inflammasome Signaling (from exercise physiology/skeletal muscle biology)
Jada Sangha; David A. Hood — Biomolecules 2026
Score: 5/10 | Pathways: NLRP3, mito-ROS-NF-kB, treatment-target

Reviews NLRP3 inflammasome activation via mitochondrial DAMPs (ROS, oxidized mtDNA) in skeletal muscle, mechanistically overlapping with the disease's mitochondrial-inflammasome axis but without SAMHD1, cGAS-STING, or IFN-I context, and exercise/myokine focus is only indirectly relevant to ME/CFS fatigue phenotype.
DOI: 10.3390/biom16081218

Systemic effects of gout flares beyond the joints. (from Rheumatology/Cardiology)
Cipolletta Edoardo; Mamas Mamas A; Abhishek Abhishek — Current opinion in rheumatology 2026
Score: 5/10 | Pathways: urate-NLRP3, NLRP3, treatment-target

Discusses gout flare-driven NLRP3/IL-1β activation and cardiovascular sequelae, directly relevant to the GOLD stream (dGTP→uric acid→MSU crystals→NLRP3) and family gout/uric acid phenotype but not tied to SAMHD1 or interferon mechanisms.
DOI: 10.1097/BOR.0000000000001183

🟢 Low Relevance (Score 3–4)

Potential specialty bridges — skim titles

Atomic-Level Strain-Engineered Piezoelectric Nanosheets for cGAS-STING Activation. (from materials science/nanomedicine oncology)
Yang Lu; Zang Pengyu; Zhang Rui; Yang Meiqi; Yu Chenghao — 2026
Score: 4/10 | Pathways: cGAS-STING, treatment-target

This paper describes a nanomaterial-based tumor immunotherapy that activates cGAS-STING via mtDNA release, sharing a mechanistic node with the disease's BLUE pathway but in an unrelated oncologic engineering context with no SAMHD1 or interferonopathy relevance.
DOI: 10.1002/anie.5643285

Mitochondrial metabolic remodelling during bacterial infection: Molecular mechanisms, cellular consequences, and therapeutic opportunities. (from Microbiology/Infectious Disease)
Kowalik Agnieszka; Paszenda Patrycja; Frątczak Agnieszka; Piwowar Adrian; Obryck — Tissue & cell 2026
Score: 4/10 | Pathways: cGAS-STING, NLRP3, NF-kB-IKK, mito-ROS-NF-kB

This review covers mitochondrial-immune crosstalk mechanisms (cGAS-STING, NLRP3, ROS-NF-kB, mitochondrial fragmentation) overlapping with the disease's core pathways, but is focused on bacterial infection biology rather than SAMHD1 dysfunction or interferonopathy syndromes.
DOI: 10.1016/j.tice.2026.103873

Gut microbiota–mitochondria–barrier–multiorgan axis: a network-based hypothesis for systemic injury (from Gastroenterology/critical care medicine)
Yachao Li; Huaijue Qiu; Xia Gao; Yanling Zhang; Qin Xia — Frontiers in Immunology 2026
Score: 4/10 | Pathways: cGAS-STING, NLRP3, mito-ROS-NF-kB, other

This paper discusses cGAS-STING and NLRP3 activation via mitochondrial DAMPs in a gut-microbiota-critical illness context, sharing core mechanistic pathways but lacking any SAMHD1, interferonopathy, or family phenotype connection.
DOI: 10.3389/fimmu.2026.1885379

Genome Editing in Primary Mammalian Cells via Electroporation of Editor RNA. (from molecular biology/gene editing methodology)
Maria Viskadourou; J. Workman; Emma V Burke; D. M. Eckley; Johannes Dohr — Journal of visualized experiments : JoVE 2026
Score: 4/10 | Pathways: prime-editing, gene-therapy-delivery

General methods paper on mRNA-based genome editing delivery in primary cells, relevant as generic platform technology for future SAMHD1 correction but not disease-specific or immune/myeloid-focused.
DOI: 10.3791/71449

FGFR4 suppresses antitumor immunity and cuproptosis by disrupting CYLD-mediated stabilization of STING and FDX1. (from Oncology (tumor immunology/cancer therapeutics))
Zhong Hongguang; Huang Ruixuan; Deng Wenyuan; Ruan Ruiwen; Dai Xiaofeng — 2026
Score: 4/10 | Pathways: cGAS-STING, treatment-target, other

This paper involves cGAS-STING pathway regulation via CYLD/FDX1/cuproptosis in cancer immunotherapy, but is oncology-focused with no connection to SAMHD1, dNTP metabolism, or interferonopathy mechanisms central to this disease profile.
DOI: 10.1016/j.canlet.2026.218790

Epithelial interferon-stimulated gene programs modulate chemotherapy sensitivity in colorectal cancer via EPSTI1. (from Oncology)
Erkan Erdogan Pekcan; Hämäläinen Emmi; Kolikova Julia; Nikupaavola Tiia; Sajnani — Oncogene 2026
Score: 4/10 | Pathways: JAK-STAT, treatment-target

Discusses JAK-STAT/ISG program and ruxolitinib in a colorectal cancer oncology context, tangentially touching interferon signaling but without SAMHD1, mitochondrial, or innate immune inflammasome mechanisms central to the disease profile.
DOI: 10.1038/s41388-026-03957-9

Dysfunction of the Neurovascular Unit in Diabetic Retinopathy: Advances from Molecular Mechanisms to Targeted Interventions. (from Ophthalmology)
Zhao Chunning; Qin Leilei; Zhang Jing; Wang Xiu — Stem cell reviews and reports 2026
Score: 3/10 | Pathways: NLRP3, other

This is a diabetic retinopathy review touching on NLRP3/mitochondrial dysfunction in a generic ophthalmology context, without any SAMHD1, interferon, or family-phenotype linkage.
DOI: 10.1007/s12015-026-11213-6

Alopecia Areata: Current and Emerging Therapies. (from Dermatology)
Domingues João; King Brett; Torres Tiago — Drugs 2026
Score: 3/10 | Pathways: JAK-STAT, treatment-target

Reviews JAK inhibitors (baricitinib) for alopecia areata, relevant as a JAK-STAT therapeutic class overlapping with interferonopathy management but not directly tied to SAMHD1 mechanism or family phenotypes.
DOI: 10.1007/s40265-026-02371-5

Integrated Multi-omics Reveals CDKN1A Suppression and Metabolic Regulation as Key Mechanisms of Huangqi Guizhi Wuwu Decoction Against Doxorubicin-Induced Cardiotoxicity. (from Cardio-oncology/pharmacology (traditional Chinese medicine))
Hou Qian; Yu Xinyue; Wu Ke; Chen Siling; Mao Xin — Cardiovascular toxicology 2026
Score: 3/10 | Pathways: ISG15-mitophagy, other

This paper on a Chinese herbal decoction mitigating doxorubicin cardiotoxicity incidentally identifies Irf7/Isg15 and apoptosis genes (Bax, Cdkn1a) but has no mechanistic connection to SAMHD1, interferonopathy, or the core inflammasome/mitochondrial pathways central to this disease profile.
DOI: 10.1007/s12012-026-10168-x

Pathway Coverage This Week

  • treatment-target: 11 papers
  • cGAS-STING: 8 papers
  • NLRP3: 7 papers
  • other: 6 papers
  • NF-kB-IKK: 3 papers
  • JAK-STAT: 3 papers
  • mito-ROS-NF-kB: 3 papers
  • VDAC1: 1 papers
  • clinical-phenotype: 1 papers
  • urate-NLRP3: 1 papers
  • prime-editing: 1 papers
  • gene-therapy-delivery: 1 papers
  • ISG15-mitophagy: 1 papers

A genome-wide map of the genetic network in monocytes that regulates type I interferon induction by the cGAS-STING pathway

The finding

Using genome-wide CRISPR screens in THP-1 monocytes, this paper maps the positive and negative regulators of IFNB1 induction downstream of cGAS-STING, comparing unprimed cells with cells pre-exposed to IFN-α to mimic ongoing inflammation. The screens reveal distinct regulatory networks in each state, including a novel role for the NCoR/SMRT corepressor components TBL1XR1 and HDAC3 in supporting IFNB1 expression, with HDAC3 promoting TBK1 activation.

Where it fits

This study speaks directly to Loop A (IFN-I/JAK-STAT) and, importantly, to the primed state that characterizes chronic interferonopathy. In SAMHD1 p.A565T, tonic IFN-I signaling establishes a primed monocyte environment—exactly the condition this screen models with IFN-α pre-treatment. The finding that distinct gene sets regulate IFNB1 in primed versus unprimed cells is critical: it suggests that the genetic circuitry sustaining chronic IFN-I production differs from that initiating it, which has implications for therapeutic targeting.

The HDAC3/TBL1XR1→TBK1 axis is particularly relevant. TBK1 is a nodal kinase in the cGAS-STING pathway, and the identification of an epigenetic corepressor complex feeding into its activation opens a new regulatory layer. In the context of SAMHD1 A565T, where IRF3/7-driven IFN-I is chronically elevated, this raises the possibility that HDAC3 or TBL1XR1 could be intervention points to dampen—rather than fully block—STING signaling, potentially reducing the smoldering IFN tone without eliminating basal innate immunity.

The resource itself is also valuable: the gene lists provide candidate modifiers for the variable expressivity seen in heterozygous SAMHD1 interferonopathy, where modifier loci may determine whether residual SAMHD1 activity is sufficient to maintain homeostasis.

Caveats

  • The screens were performed in THP-1 cells (a monocytic cell line), not primary monocytes or SAMHD1-mutant cells; the regulatory architecture may differ in primary cells or in the context of SAMHD1 deficiency.
  • The readout is IFNB1 transcription only; it does not capture post-transcriptional regulation, protein-level control, or the full ISG repertoire downstream of IFNAR signaling.
  • The study identifies regulators of cGAS-STING-induced IFN, but does not address whether these same genes modulate the NLRP3 arm (Loop B) or the paracrine IFN-γ feedback (Loop C).

What to watch

Whether HDAC3/TBL1XR1 inhibition selectively reduces primed-state IFNB1 induction in SAMHD1-deficient monocytes—and whether that translates to suppression of the broader ISG signature without disrupting the NLRP3 axis.

Source: A genome-wide map of the genetic network in monocytes that regulates type I interferon induction by the cGAS-STING pathway — Science Signaling 2026.

Case of Aicardi-Goutières syndrome diagnosed in adulthood on whole-genome sequencing

The finding

This case report describes a 31-year-old woman with compound heterozygous variants in the ADAR gene (p.Pro193Ala and p.Ser371Cysfs*3), diagnosed with Aicardi-Goutières syndrome (AGS) only in adulthood via whole-genome sequencing. Her presentation was non-classical: normal early milestones, progressive ataxia and hypotonia from age 3, later spasticity, dystonia, learning difficulties, and — notably — significant cardiac valvular calcification. She has been referred for baricitinib (JAK1/JAK2 inhibitor) treatment.

Where it fits

This case speaks most directly to Loop A (interferon/JAK-STAT) and the clinical outcome layer of the model. ADAR mutations are a canonical AGS cause, acting upstream of the same type I interferon amplification that SAMHD1 p.A565T drives through cGAS–STING sensing and IRF3-dependent IFN-I production. The referral for baricitinib — a JAK1 inhibitor — is the key translational point: it directly tests the JAK-inhibitor-responsive arm of Loop A, the same intervention predicted to dampen tonic IFN-I signaling in SAMHD1 A565T.

The extracerebral calcification is also relevant. In the SAMHD1 model, calcification is linked to the mitochondrial/NLRP3 arm (Loop B), where dNTP pool expansion drives POLG stress and NLRP3 licensing. That this ADAR-related AGS patient shows prominent valvular calcification suggests calcification may be a shared downstream consequence of chronic interferonopathy rather than a gene-specific effect — a useful cross-validation for the model's claim that Loop B is partly JAK-resistant and may require separate targeting.

Caveats

  • This is a single case with ADAR variants, not SAMHD1 p.A565T; the relevance is analogical, not direct.
  • Compound heterozygous (likely null) ADAR mutations differ mechanistically from a heterozygous partial loss-of-function SAMHD1 allele; the smoldering "non-acute chronic inflammation" phenotype may not translate.
  • The baricitinib referral is reported, not a treatment outcome; no response data are presented.

What to watch

Whether baricitinib treatment in this patient suppresses the ISG signature and whether calcification stabilizes or progresses — the latter would speak to whether JAK inhibition alone can touch Loop B, a central open question for the SAMHD1 model's two-rescue-point claim.

Source: Case of Aicardi-Goutières syndrome diagnosed in adulthood on whole-genome sequencing — 2026.

Emerging microbiome–mitochondria crosstalk in host defense and infectious diseases: mechanistic insights into NLRP3 inflammasome activation and mtDNA-mediated immunomodulation

The finding

This review synthesizes recent evidence that gut microbiota metabolites—short-chain fatty acids, trimethylamine, and indole derivatives—directly modulate mitochondrial function and reactive oxygen species (ROS) production, which in turn gates NLRP3 inflammasome activation. The authors also consolidate findings that dysbiosis promotes mitochondrial stress and mtDNA release, with mtDNA acting as a damage-associated molecular pattern that can engage both cGAS-STING and NLRP3 signaling, linking gut microbial shifts to systemic inflammation across colitis, neurodegeneration, and sepsis.

Where it fits

This review speaks directly to Loop B (mitochondrial/NLRP3) and provides a critical checkpoint insight relevant to SAMHD1 A565T. The paper's central claim—that mitochondrial ROS and mtDNA fragmentation are upstream licensing events for NLRP3—mirrors the model's proposed mechanism whereby POLG replisome stress generates oxidized mtDNA (8-OHdG) that primes NLRP3 rather than cGAS. The review's emphasis on PINK1/Parkin-mediated mitophagy as a brake on this pathway is directly relevant: in the SAMHD1 model, ISG15 ISGylates MFN1/2 and BECN1 to block mitophagy, creating a self-sustaining loop. The review also reinforces the dual-sensor logic—mtDNA can hit both cGAS-STING and NLRP3 via distinct routes—which is the model's central testable claim. Finally, the microbiome–mitochondria axis suggests an environmental modifier: gut-derived metabolites could tune the threshold for NLRP3 licensing in SAMHD1 carriers, potentially explaining variable penetrance.

Caveats

  • This is a review, not primary data; the mechanistic links are synthesized from disparate studies, often in different cell types or disease models.
  • The microbiome–mitochondria–NLRP3 connections are largely demonstrated in non-SAMHD1 contexts (colitis, sepsis); extrapolation to SAMHD1 A565T is inferred, not tested.
  • The review does not address heterozygous vs. homozygous loss-of-function, nor does it quantify how much mitochondrial stress is needed to cross the NLRP3 activation threshold.

What to watch

Does modulating the gut microbiome—via probiotics or metabolite supplementation—alter NLRP3-dependent IL-18/IL-1β output in SAMHD1 models? If so, the microbiome becomes a druggable upstream node for Loop B, potentially complementing JAK inhibition that targets Loop A.

Source: Emerging microbiome–mitochondria crosstalk in host defense and infectious diseases: mechanistic insights into NLRP3 inflammasome activation and mtDNA-mediated immunomodulation — Frontiers in Cellular and Infection Microbiology 2026.