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July 2026

SAMHD1 Research Digest — 2026-07-29

Generated by samhd1_monitor | Model: claude-sonnet-5

Summary: 12 papers evaluated | 3 high-relevance (≥7) | 8 medium (5–6) | 1 low (3–4) | 0 scored <3

🔴 High Relevance (Score 7–10)

Auto-added to Zotero (threshold ≥6)

Mitophagy mitigates mitochondrial DNA-induced activation of cGAS-STING in autoimmune thyroiditis (from Endocrinology/Rheumatology—autoimmune thyroiditis model provides orthogonal evidence for cGAS-STING-driven tissue-specific autoimmunity that bridges to systemic interferonopathy phenotype in multi-system SAMHD1 families.)
Xiao-Chen Xie; Yang Guo; Ran Guo; Yong-Ze Li; Shan-Shan Wang — Nature Communications 2026
Score: 8/10 | Pathways: cGAS-STING, VDAC1, ISG15-mitophagy, POLG-mtDNA, mito-ROS-NF-kB, treatment-target, clinical-phenotype

Directly demonstrates mtDNA-cGAS-STING axis driving autoimmune disease via impaired mitophagy (PINK1/Parkin/TAX1BP1), mechanistically overlapping with the RED and BLUE loops in SAMHD1 A565T haploinsufficiency; identifies STING inhibition as therapeutic target applicable to convergent interferonopathy.
DOI: 10.1038/s41467-026-76047-9

NLRP3 Inhibitor KBD3536 Attenuates Acute Inflammation, Radiation-Induced Skin Injury, and Early Metabolic Dysfunction in Preclinical Models. (from Pharmacology/medicinal chemistry (NLRP3 inhibitor drug discovery and preclinical efficacy testing))
Qian Xinying; Ye Fei; Li Zhiyong; Chu Hongzhu; Xu Zeng — Pharmaceuticals (Basel, Switzerland) 2026
Score: 7/10 | Pathways: urate-NLRP3, NLRP3, NF-kB-IKK, treatment-target, clinical-phenotype

KBD3536 is a novel NLRP3 inhibitor with demonstrated efficacy in MSU-induced acute inflammation (gouty arthritis) and HFD-induced metabolic dysfunction—two pathologies directly implicated in the SAMHD1 A565T family phenotype (dGTP → purine catabolism → uric acid → MSU-NLRP3 axis; hepatic steatosis via IRF7-metabolic reprogramming); the paper provides preclinical validation of NLRP3 inhibition as a therapeutic strategy for this converged interferonopathy-metabolic syndrome.
DOI: 10.3390/ph19071083

CRISPR screening identifies GNPTAB as a noncanonical STING activator driving cellular senescence. (from Cell biology/gerontology—lysosomal biology and senescence mechanotransduction, not traditionally part of immunology or rheumatology training.)
Yin Jian; Gao Yizhou; Jing Yaobin; Jiang Xiaoyu; Wang Feibo — Protein & cell 2026
Score: 7/10 | Pathways: cGAS-STING, NF-kB-IKK, mTOR-lysosomal, treatment-target

GNPTAB-STING noncanonical activation via direct protein-protein interaction (E1119 interface) provides a novel upstream STING priming mechanism independent of canonical cGAS-mtDNA sensing; this represents an alternative route to STING/TBK1/NF-κB axis hyperactivation relevant to the BLUE and NF-κB crosstalk loops in A565T interferonopathy, with actionable therapeutic potential (STING-GNPTAB interface antagonism) for suppressing senescence-associated STING amplification.
DOI: 10.1093/procel/pwag049

🟡 Medium Relevance (Score 5–6)

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

DNAJB12/14 redox switching directs chaperone- and Bax/Bak-dependent ER protein reflux. (from Cell biology / ER stress and proteostasis; redox biochemistry)
Abu Madegam Laila; Gavriel Noa; Adebisi Raifu Tolulope; Igbaria Aeid — Redox biology 2026
Score: 6/10 | Pathways: BIK-cancer, mTOR-lysosomal, NF-kB-IKK, apoptosis-autophagy switch

BIK-mediated BAX/BAK recruitment to ER during severe ER stress mechanistically overlaps with the apoptosis-autophagy switch dysregulated in SAMHD1 haploinsufficiency, where ISGylation of BH3-only proteins and mitochondrial damage drive cell death; redox-sensitive DNAJB chaperone control of proteostasis and ER-to-cytosol signaling may modulate the severity of interferonopathy-driven ER stress in this family.
DOI: 10.1016/j.redox.2026.104324

Pectolinarigenin Attenuates LPS-Induced Lung Inflammation and Injury with Reduced HDAC3/NF-κB/NLRP3 Signaling. (from Pulmonology/immunotoxicology; plant natural products pharmacology)
Kim Danbee; Lee Dong-Keon; Park Jeong-Ran — Antioxidants (Basel, Switzerland) 2026
Score: 6/10 | Pathways: NLRP3, NF-kB-IKK, NF-kB-NLRP3-priming, treatment-target

Pectolinarigenin directly modulates the HDAC3/NF-κB/NLRP3 axis in LPS-induced inflammation, addressing two key steps in the proband's pathophysiology: NF-κB transcriptional priming of NLRP3 (Signal 1) and NLRP3 inflammasome activation (Signal 2); HDAC3 inhibition is a mechanistically novel approach to breaking the NF-κB–NLRP3 feed-forward loop and reducing mitochondrial ROS-driven inflammation, though the study uses acute LPS challenge rather than the chronic mitochondrial dNTP–oxMtDNA–NLRP3 circuit specific to SAMHD1 haploinsufficiency.
DOI: 10.3390/antiox15070898

Evolutionary history and recombination in the mitochondrial carrier SLC25 superfamily analyzed by similarities in the exon and transmembrane α‐helix sequences (from Evolutionary biology / structural proteomics)
Magnus Monné; D. V. Miniero; R. Calvello; A. Cianciulli; Luigi Palmieri — Protein Science : A Publication of the Protein Society 2026
Score: 6/10 | Pathways: mito-dNTP-transport, nucleotide-rewiring, other

This evolutionary/structural analysis of SLC25 superfamily (including PNC1/PNC2 nucleotide carriers) provides mechanistic foundation for understanding how substrate-specific subfamilies arose, directly relevant to the PNC1/2-mediated mitochondrial dNTP import bypass that drives NLRP3 hyperactivation in SAMHD1 haploinsufficiency; exon recombination patterns could illuminate functional specialization of dNTP transporters.
DOI: 10.1002/pro.70727

Synthetic Toll-Like Receptors for Control of Innate Immunity With Far-Red Light. (from Synthetic optogenetics/photobiology—a tool discipline offering potential mechanistic insight and future targeting strategy for the NF-κB and interferon regulatory axis but without direct mitochondrial, dNTPase, or disease-specific validation.)
Leopold Anna V; Verkhusha Vladislav V — Advanced science (Weinheim, Baden-Wurttemberg, Germany) 2026
Score: 6/10 | Pathways: NF-kB-IKK, IRF7-metabolic, treatment-target

Synthetic TLR optogenetics with MyD88→NF-κB/IRF3/IRF7 axis reprogramming is mechanistically adjacent to the NF-κB priming of NLRP3 and the dual IKKε-driven NF-κB + IRF7 crosstalk that sustains the convergent interferon–mitochondrial syndrome in SAMHD1 p.A565T haploinsufficiency; optical dissection of TLR→MyD88→NF-κB/IRF signaling could reveal druggable nodes in the IKK-NEMO complex and IRF7-metabolic amplification loop.
DOI: 10.1002/advs.202520640

Targeting the NLRP3/Caspase-1 pyroptotic pathway exacerbates insulin resistance upon exposure to nanoplastics with different surface chemistries. (from Environmental toxicology and metabolic disease; bridges to rare disease through convergent NLRP3-inflammasome-insulin-resistance axis and mitochondrial dysfunction phenocopy of SAMHD1 haploinsufficiency.)
Yao Xinxin; Cao Yu; Lin Sue; Chen Shihua; Xie Feiqin — Journal of hazardous materials 2026
Score: 6/10 | Pathways: NLRP3, mitochondrial-ROS-NF-kB, oxidative-stress-mtDNA, metabolic-dysfunction-insulin-resistance, inflammasome-pyroptosis, other

Paper demonstrates NLRP3/caspase-1 pyroptotic activation downstream of nanoplastic-induced mitochondrial dysfunction and cytosolic mtDNA accumulation in metabolic stress (hyperglycemia/insulin resistance), directly modeling the PURPLE-loop mechanism (ox-mtDNA → NLRP3) and BLUE-loop (mtDNA escape → inflammasome) operative in SAMHD1 A565T haploinsufficiency; validates NLRP3 inhibition as partial rescue strategy for metabolic phenotypes, but lacks SAMHD1, dNTPase, or dNTP-mediated mechanism, and uses exogenous environmental trigger rather than genetic haploinsufficiency.
DOI: 10.1016/j.jhazmat.2026.143078

Astilbin Alleviates Gouty Arthritis via Regulating NLRP3 Inflammasome and NF-κB Signaling Pathway: A Comprehensive Study on In Vitro and In Vivo Experimental Models. (from Rheumatology/Pharmacology (natural product anti-inflammatory); mechanism-of-action study demonstrating dual NLRP3–NF-κB inhibition in gouty arthritis model, transferable to dNTP-driven NLRP3 hyperactivation in SAMHD1-deficient states.)
Zhang Xiaoxi; Fu Gaoyang; Zhao Xinyu; Huang Yan; Li Fenfen — Nutrients 2026
Score: 6/10 | Pathways: urate-NLRP3, NLRP3, NF-kB-IKK, NF-kB-NLRP3-priming, treatment-target

Astilbin suppresses MSU-crystal–induced NLRP3 inflammasome and NF-κB signaling (P-p65, P-IKKα, P-IκBα, cleaved-caspase-1), directly targeting the GOLD pathway (dGTP → uric acid → MSU → NLRP3) and the NF-κB priming axis that sustains IL-1β autocrine amplification in SAMHD1 haploinsufficiency; relevant as a potential adjunctive therapeutic for the inflammatory arm of convergent interferon–mitochondrial syndrome in this family.
DOI: 10.3390/nu18142360

Blood transcriptome bridges orthogonal immunotypes and gut microbiome enterotypes in humans. (from Microbiome/Metabolomics)
Affaticati Fabio; Ha My K; Gehrmann Thies; De Boeck Ilke; Kuznetsova Mariia — Cell reports 2026
Score: 6/10 | Pathways: NF-kB-IKK, JAK-STAT, NLRP3, clinical-phenotype

Blood transcriptome integration identifies two distinct inflammatory profiles—interferon-driven versus NF-κB/IL-6-driven—that directly map to the divergent activation streams (BLUE interferon loop vs. PURPLE/GOLD NLRP3 loops) in SAMHD1 A565T haploinsufficiency; gut microbiota-immune axis bridging is relevant to family's reported gastrointestinal heterogeneity and immunotype stratification in interferonopathy populations.
DOI: 10.1016/j.celrep.2026.117752

Evaluation of Zebularine as a Potential DNA Methyltransferase 1 Inhibitor Associated With SAMHD1 Expression in Cancer Cells (from Oncology)
Muhammad Zeeshan Ahmed; Mahnoor Fatima; Ayesha Shahbaz; Zeeshan Mutahir — ChemistrySelect 2026
Score: 5/10 | Pathways: BIK-cancer, SAMHD1, treatment-target

Zebularine modulates SAMHD1 expression in prostate cancer cells (relevant to BIK-prostate axis and SAMHD1 as tumor suppressor in family phenotype), but mechanistic connection is via DNMT1 epigenetic silencing rather than dNTPase activity, mitochondrial dysfunction, or interferonopathy pathways central to A565T haploinsufficiency.
DOI: 10.1002/slct.73893

🟢 Low Relevance (Score 3–4)

Potential specialty bridges — skim titles

VRK3 promotes KSHV infection by suppressing the antiviral type I interferon response. (from Virology/Oncology (KSHV tropism and persistent infection pathogenesis, not immunometabolic or rare disease))
Yu Caroline J; Damania Blossom — PLoS pathogens 2026
Score: 3/10 | Pathways: IRF3, cGAS-STING, JAK-STAT, other

VRK3 suppresses IRF3 and TBK1 activation in KSHV infection, which intersects the cGAS-STING→IRF3→IFN-I axis (BLUE Loop), but lacks SAMHD1 involvement, mitochondrial pathology, dNTP metabolism, NLRP3, or direct relevance to the A565T haploinsufficiency mechanism driving the convergent interferon–mitochondrial syndrome.
DOI: 10.1371/journal.ppat.1014400

Pathway Coverage This Week

  • treatment-target: 7 papers
  • NF-kB-IKK: 7 papers
  • NLRP3: 5 papers
  • cGAS-STING: 3 papers
  • clinical-phenotype: 3 papers
  • other: 3 papers
  • urate-NLRP3: 2 papers
  • mTOR-lysosomal: 2 papers
  • BIK-cancer: 2 papers
  • NF-kB-NLRP3-priming: 2 papers
  • JAK-STAT: 2 papers
  • VDAC1: 1 papers
  • ISG15-mitophagy: 1 papers
  • POLG-mtDNA: 1 papers
  • mito-ROS-NF-kB: 1 papers
  • apoptosis-autophagy switch: 1 papers
  • mito-dNTP-transport: 1 papers
  • nucleotide-rewiring: 1 papers
  • IRF7-metabolic: 1 papers
  • mitochondrial-ROS-NF-kB: 1 papers
  • oxidative-stress-mtDNA: 1 papers
  • metabolic-dysfunction-insulin-resistance: 1 papers
  • inflammasome-pyroptosis: 1 papers
  • SAMHD1: 1 papers
  • IRF3: 1 papers

↩ Re-run 08:33 UTC | Model: claude-sonnet-5

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

🟡 Medium Relevance

Multiple Roles of G3BP1 in Regulating STING-Dependent Interferon and Cytokine Induction by Cytosolic dsDNA and HSV-1 Infection. (from Virology/cell stress biology)
Trupti Devale; Praveen Manivannan; K. Malathi — Viruses 2026
Score: 6/10 | Pathways: cGAS-STING, treatment-target

Details G3BP1 as a regulator of cGAS-STING signaling (STING Golgi trafficking, IFN/cytokine output) directly relevant to the BLUE loop mechanism underlying the SAMHD1 interferonopathy, though it does not involve SAMHD1 itself.
DOI: 10.3390/v18070719

SAMHD1 Research Digest — 2026-07-26

Generated by samhd1_monitor | Model: claude-sonnet-5

Summary: 31 papers evaluated | 5 high-relevance (≥7) | 16 medium (5–6) | 10 low (3–4) | 0 scored <3

🔴 High Relevance (Score 7–10)

Auto-added to Zotero (threshold ≥6)

Modeling calcific aortic valve disease with engineered human valve tissues identifies SAMHD1 as a therapeutic target. (from Cardiology/bioengineering (tissue engineering and valvular calcification))
Meng Xiangfu; Zhou Qian; Zhu Zijin; Qiao Weihua; Geng Bingchuan — Biomaterials 2026
Score: 7/10 | Pathways: treatment-target, clinical-phenotype, other

This paper identifies SAMHD1 as a novel therapeutic target in calcific aortic valve disease via WGCNA-driven small-molecule inhibition, extending SAMHD1's disease relevance beyond interferonopathy into a cardiovascular/osteogenic context pertinent to potential cardiac phenotypes in the family.
DOI: 10.1016/j.biomaterials.2026.124432

The mitochondrial DNA signal in rheumatoid arthritis: From metabolic victim to inflammatory driver. (from Rheumatology)
Zhang Ruoyi; Song Zhijie; Xin Qimeng; Xing Wenbin; Zhang Wenlan — Biochemical and biophysical research communications 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, POLG-mtDNA, clinical-phenotype, treatment-target

Reviews the mtDNA damage-release-cGAS/STING-NLRP3 axis driving RA inflammation, mechanistically parallel to the purple/blue loops in the SAMHD1 syndrome and directly relevant to the family's rheumatoid arthritis phenotype.
DOI: 10.1016/j.bbrc.2026.154304

Case of Aicardi-Goutières syndrome diagnosed in adulthood on whole-genome sequencing. (from Neurology/Genetics)
Cobb Lewis; Kumar Jayant; Roy Amit; Walsh Sarah; Sheerin Una-Marie — BMJ neurology open 2026
Score: 7/10 | Pathways: AGS-spectrum, cGAS-STING, JAK-STAT, treatment-target, clinical-phenotype

This adult-diagnosed ADAR-related AGS case with atypical presentation, cardiac calcification, and baricitinib consideration directly parallels the type I interferonopathy spectrum and JAK inhibitor treatment strategy relevant to SAMHD1-driven disease.
DOI: 10.1136/bmjno-2025-001407

HTLV-1 Tax induces PINK1-PRKN/parkin-dependent mitophagy to mitigate activation of the CGAS-STING1 pathway. (from Virology/hematology (HTLV-1-associated leukemia and neuroinflammatory disease))
Mohanty Suchitra; Suklabaidya Sujit; Mnatsakanyan Nelli; Jacobson Steven; Harhaj — Autophagy 2026
Score: 7/10 | Pathways: cGAS-STING, ISG15-mitophagy, NF-kB-IKK, treatment-target

This paper demonstrates PINK1-PRKN-dependent mitophagy (via NEMO/IKK interaction) suppressing cGAS-STING1-driven type I interferon activation in a viral infection context, directly paralleling the mitophagy-block/IFN-I-amplification mechanism central to the SAMHD1 syndrome model (RED/BLUE loops) even though the driver here is HTLV-1 Tax rather than SAMHD1 dysfunction.
DOI: 10.1080/15548627.2026.2707897

Type I interferonopathies: 15 years after the concept-news and views. (from Rheumatology)
S. Khaldi-Plassart; I. Melki; M. Frémond — Current opinion in rheumatology 2026
Score: 7/10 | Pathways: cGAS-STING, AGS-spectrum, treatment-target, clinical-phenotype, JAK-STAT

This review covers type I interferonopathy mechanisms (STING/IFNAR signaling, TLR pathways, clinical penetrance variability, JAK inhibitor therapeutics) directly relevant to the SAMHD1-driven IFN-I overproduction and AGS-spectrum disorder underlying the family syndrome, though it does not address SAMHD1 specifically.
DOI: 10.1097/BOR.0000000000001179

🟡 Medium Relevance (Score 5–6)

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

Fibroblast S1PR2 Amplifies NLRP3 Inflammasome Activation Under Pressure Overload. (from Cardiology)
Zhou Caixia; Liu Zhihao; Wang Zhiru; Cui Zekun; Wang Qian — Hypertension (Dallas, Tex. : 1979) 2026
Score: 6/10 | Pathways: NLRP3, mito-ROS-NF-kB, treatment-target

Demonstrates mitochondrial damage (DRP1 fission, mitophagy suppression) driving mtDNA leakage and NLRP3 activation, mechanistically parallel to the SAMHD1 mitochondrial-inflammasome axis though in cardiac fibroblasts rather than SAMHD1-deficient immune cells.
DOI: 10.1161/HYPERTENSIONAHA.126.27475

Isoalantolactone targets NLRP3 to disrupt NLRP3-NEK7 interaction and suppress inflammasome activation. (from pharmacology/drug discovery)
Shi Yuanfang; Zhu Xiaoyun; Sun Meng; Yang Yang; Lin Siwei — Biochemical pharmacology 2026
Score: 6/10 | Pathways: NLRP3, urate-NLRP3, treatment-target

This paper identifies a small-molecule NLRP3 inhibitor effective against MSU-induced gout and MASLD, directly relevant to the GOLD pathway (dGTP→uric acid→MSU→NLRP3) and offering a potential therapeutic candidate for the syndrome's inflammasome-driven pathology.
DOI: 10.1016/j.bcp.2026.118165

Interferon-related gene expression defines disease activity, organ involvement and treatment response in juvenile dermatomyositis. (from Pediatric rheumatology (juvenile dermatomyositis))
Codes-Méndez Helena; Cuyx Senne; Syntakas Aris E; Barmpakou Afroditi; Moraitis E — Rheumatology (Oxford, England) 2026
Score: 6/10 | Pathways: JAK-STAT, treatment-target, clinical-phenotype

Demonstrates type-I interferon-related gene expression (ISGs, IFI27, IFI44L, RSAD2) as biomarker of disease activity and JAK inhibitor (baricitinib) response, directly reinforcing the IFN-I/JAK-STAT arm of the interferonopathy mechanism relevant to SAMHD1 pathway and treatment translation, though not SAMHD1-specific.
DOI: 10.1093/rheumatology/keag384

Glycerol-3-Phosphate Attenuates Hypoxic-Ischemic Brain Injury via Modulation of Microglia-Mediated Neuroinflammation. (from Neurology/perinatal neonatology)
Qin Dani; Lei Yong; Le Meini; Cheng Mengke; Zhao Yingmin — Neurochemical research 2026
Score: 6/10 | Pathways: cGAS-STING, NF-kB-IKK, treatment-target, mito-ROS-NF-kB

Demonstrates cGAS-STING-TBK1-NF-kB axis driving microglial neuroinflammation and mitochondrial dysfunction, directly relevant to the same core pathway implicated in the SAMHD1 A565T interferon-mitochondrial syndrome, with therapeutic implications for neuroinflammatory phenotypes seen in the family (AuDHD, ME/CFS-like fatigue).
DOI: 10.1007/s11064-026-04848-x

Aspirin Inhibits the cGAS-STING Signaling Pathway to Ameliorate the Development of Aortic Aneurysm and Dissection. (from Vascular surgery/cardiology (aortic aneurysm and dissection))
Zeng Yi-Fan; Wang Qiu-Guo; Qi Zhen; Li Jing-Yu; Duan Zhi-Cheng — Arteriosclerosis, thrombosis, and vascular biology 2026
Score: 6/10 | Pathways: cGAS-STING, treatment-target

Demonstrates a novel cGAS-STING axis (via cGAS acetylation) driving mitochondrial/ferroptotic vascular pathology and its pharmacological inhibition by aspirin, directly relevant to the Blue loop mechanism though in a cardiovascular rather than immune context.
DOI: 10.1161/ATVBAHA.126.324930

Single-Cell Analysis of Residual Esophageal Squamous Cell Carcinoma After Neoadjuvant Immunochemotherapy Reveals TFAM-Mediated Immunoregulation in Dendritic Cells. (from Oncology (esophageal squamous cell carcinoma immunotherapy))
Chen Linyan; Feng Tang; Zhou Jianfeng; Zeng Hao; Lai Yutian — Cancer research 2026
Score: 6/10 | Pathways: cGAS-STING, treatment-target, other

This paper demonstrates TFAM deficiency in dendritic cells activating the STING-TBK1-IRF3 pathway to promote anti-tumor immunity, directly relevant to the mitochondrial-cGAS-STING-IFN-I axis central to the SAMHD1 mechanism though in an oncologic rather than interferonopathy context.
DOI: 10.1158/0008-5472.CAN-25-4738

Stub1 promotes chaperone-mediated autophagy to suppress antiviral immunity. (from Virology/cell biology (autophagy regulation))
Liu Hongyang; Huang Li; Weng Changjiang — Autophagy 2026
Score: 6/10 | Pathways: cGAS-STING, JAK-STAT, treatment-target

This paper describes a novel TBK1 degradation pathway (CMA via Stub1) that directly regulates the cGAS-STING-TBK1-IFN-I axis central to the SAMHD1 mechanism, relevant to interferonopathy modulation though not SAMHD1-specific.
DOI: 10.1080/15548627.2026.2667376

Dual-regulation of mitophagy and cytosolic mtDNA-induced inflammation for the treatment of inflammatory bone loss. (from orthopedics/bone regeneration)
Zheng Kaiwen; Che Benchi; Cui Yongzhi; Yang Han; Xiang Yu — 2026
Score: 6/10 | Pathways: cGAS-STING, ISG15-mitophagy, treatment-target, clinical-phenotype

Directly models the mtDNA-cGAS-STING-inflammation-mitophagy (PINK1) axis central to the BLUE/RED streams and demonstrates a dual STING/PINK1 exosome therapeutic, relevant to osteoporosis noted in family phenotype tracking though not SAMHD1-specific.
DOI: 10.1016/j.freeradbiomed.2026.07.031

Tumor microenvironment-responsive manganese nanoplatform amplifies cGAS-STING via metabolic-metal synergy for immunotherapy. (from Oncology/nanomedicine)
Zhou Yanlin; Wu Ziyi; Zheng Tao; Luo Shunhong; Zhang Lu — 2026
Score: 6/10 | Pathways: cGAS-STING, treatment-target

Demonstrates mitochondrial fragmentation-driven mtDNA leakage activating cGAS-STING (mirroring the BLUE/VDAC1 loop) in an oncology nanomedicine context, offering mechanistic and therapeutic parallels though not SAMHD1-specific.
DOI: 10.1016/j.jconrel.2026.115197

Mitochondria-targeted MXene-based nanozymes promote mitophagy and inhibit mtDNA-triggered cGAS/STING inflammation in osteoarthritis. (from Orthopedics/Nanomedicine)
Li Tiancheng; Zheng Ao; Zhu Cheng; Li Yixin; Yang Zitong — 2026
Score: 6/10 | Pathways: cGAS-STING, treatment-target

Demonstrates a nanozyme therapeutic that restores mitophagy and blocks mtDNA-driven cGAS/STING inflammation, directly reinforcing the disease model's Loop A mechanism though in an unrelated joint disease context.
DOI: 10.1016/j.bioactmat.2026.07.010

Engineering-Modulated Molybdenum Enzymes Strategy for Tumor-Specific Metabolic-Immunotherapy. (from oncology/nanomedicine)
Pan Xiaoxiao; Pei Zifan; Wu Jie; Jiang Nan; Li Qian — 2026
Score: 6/10 | Pathways: cGAS-STING, urate-NLRP3, treatment-target

This oncology nanomedicine paper demonstrates mtDNA release activating cGAS-STING and purine metabolism driving uric acid elevation as an immune activator, mechanistically paralleling the PURPLE/GOLD and BLUE streams (dGTP-uric acid-MSU-NLRP3 and mtDNA-cGAS-STING) in the SAMHD1 syndrome despite being applied in a cancer immunotherapy context.
DOI: 10.1002/advs.76726

Phase-dependent dynamics of circulating cell-free mitochondrial DNA reflect distinct immunometabolic states (from Tropical medicine/infectious disease and pediatric cardiac surgery biomarker research)
Karen Alessandra Rodrigues; Emilly Henrique dos Santos; Gabriel Acca Barreira; M — Revista do Instituto de Medicina Tropical de São Paulo 2026
Score: 6/10 | Pathways: VDAC1, NLRP3, treatment-target, clinical-phenotype

Circulating cell-free mtDNA as a DAMP driving innate immune activation is directly relevant to the BLUE/PURPLE mitochondrial escape and NLRP3 activation loops central to the SAMHD1 interferon-mitochondrial syndrome, though it does not address SAMHD1 itself.
DOI: 10.1590/s1678-9946202668048

Severe Antenatal Presentation of a Novel Dnase2 Mutation in a Preterm Omani Neonate: Expanding the Clinical Spectrum of an Ultra-Rare Interferonopathy (from Neonatology/Pediatric Genetics)
Ruqaiya Al Jashmi; Marya Al Barumi; S. Al Abrawi; Alyaa Al Mughairy; Aiman Al Ja — Cureus 2026
Score: 6/10 | Pathways: cGAS-STING, JAK-STAT, AGS-spectrum, clinical-phenotype, pregnancy-fetal, treatment-target

DNASE2 deficiency is a type I interferonopathy in the same AGS-spectrum family of diseases as SAMHD1 mutations, sharing cGAS-STING-driven IFN-I pathology and JAK inhibitor responsiveness, with fetal/neonatal presentation relevant to the pregnancy-interferonopathy phenotype tracking axis.
DOI: 10.7759/cureus.111043

Sex-specific differences of amlexanox in a mouse model for atherosclerosis and MASLD. (from Cardiometabolic/hepatology research on IKKε inhibition)
Mungo Eleonora; Haß Michelle; Benning Denis; Schmid Tobias; Kuntschar Silvia — Molecular metabolism 2026
Score: 5/10 | Pathways: NF-kB-IKK, clinical-phenotype

IKKε (a kinase explicitly named in the NF-κB crosstalk mechanism as dual NF-κB/IRF3 activator) is targeted pharmacologically here, showing sex-specific metabolic/inflammatory effects on MASLD and atherosclerosis, relevant background to the IKKβ/IKKε axis but without SAMHD1 or interferon pathway data.
DOI: 10.1016/j.molmet.2026.102426

Editing Around the Target: Epitope Engineering to Protect Stem Cell Grafts. (from Gene therapy/hematology-oncology)
Baek Joanne; Casirati Gabriele; Genovese Pietro; Gill Saar I — Blood advances 2026
Score: 5/10 | Pathways: prime-editing, gene-therapy-delivery

Reviews base/prime editing epitope engineering in HSPCs, relevant as a generic delivery/correction platform potentially applicable to correcting SAMHD1 missense variants in myeloid cells but not disease-specific.
DOI: 10.1182/bloodadvances.2025018227

Efficient CRISPR/Cas9-mediated homology independent sequence replacement in vivo and non-dividing primary cells (from genome editing / gene therapy engineering)
Dang Tu Ngoc; Roman Alexandra; Zimmer Anja; Lebedin Mikhail; Bahry Ella — preprint (preprint) 2026
Score: 5/10 | Pathways: gene-therapy-delivery, prime-editing

This paper describes a novel homology-independent CRISPR/Cas9 sequence replacement platform (REPLACE) using eVLP/AAV delivery in non-dividing cells, relevant as a general gene correction strategy applicable to correcting missense variants like SAMHD1 A565T though not directly tested on it.
DOI: 10.64898/2026.07.24.740048

🟢 Low Relevance (Score 3–4)

Potential specialty bridges — skim titles

Alopecia areata: Mechanisms, targeted therapies, and translational challenges. (from Dermatology)
Kumar Virender; Sahoo Saurabh; Kumar Pawan — Current opinion in pharmacology 2026
Score: 4/10 | Pathways: JAK-STAT, treatment-target

AA pathogenesis and JAK inhibitor therapy (baricitinib) overlap mechanistically with the IFN-I/JAK-STAT axis relevant to SAMHD1 interferonopathy, but the paper is otherwise unrelated to SAMHD1 or mitochondrial-inflammasome mechanisms.
DOI: 10.1016/j.coph.2026.102635

Gene therapy approaches for inborn errors of immunity: from bench to bedside. (from gene therapy/genetic medicine)
Dara Jasmeen; Booth Claire — Expert opinion on biological therapy 2026
Score: 4/10 | Pathways: gene-therapy-delivery

General review of gene therapy for inborn errors of immunity (retroviral, lentiviral, CRISPR, base/prime editing) provides background relevance to future correction strategies for SAMHD1 variants but has no disease-specific or mechanistic content.
DOI: 10.1080/14712598.2026.2710870

Mitochondrial stress-induced cuproptosis: a metabolic bridge to reprogramming the GBM immune microenvironment. (from Oncology (neuro-oncology/GBM immunotherapy))
Li Wenyang; Lv Yaqing; Wang Guanrong; Lan Xiaolei; Ren Leina — 2026
Score: 4/10 | Pathways: cGAS-STING, other

Discusses mtDNA release triggering cGAS-STING/type I IFN in GBM cuproptosis context, sharing a core mechanistic node but unrelated to SAMHD1 dNTPase biology or the family phenotype spectrum.
DOI: 10.1007/s13402-026-01254-x

Prime editing in neuropsychiatric disorders: From mutation‐specific target selection to clinical translation (from Neurology/gene therapy)
Tianshan Ji; Yuan Zhang; Jinyi Zhao; Yi Lu; Chengkun Wang — Neuroprotection 2026
Score: 4/10 | Pathways: prime-editing, gene-therapy-delivery

General review of prime editing for neuropsychiatric monogenic disorders offers relevant delivery/technology context but no direct SAMHD1, immune, or mitochondrial pathway content and focuses on neurons rather than myeloid/immune cells.
DOI: 10.1002/nep3.70041

A poly(I:C)/QS-21-based in situ vaccine synergizes with anti-PD-1 therapy to overcome tumor immunoresistance. (from oncology/cancer immunotherapy)
Zhang Wenbo; Ni Xinrui; Zhuo Luoyi; Liu Jiangrui; Yang Guang — Cell reports. Medicine 2026
Score: 3/10 | Pathways: cGAS-STING, treatment-target

This oncology immunotherapy paper touches TBK1-IRF3-type I interferon axis (relevant pathway component) but in a tumor vaccine/anti-PD-1 context unrelated to SAMHD1 haploinsufficiency or the family's interferonopathy syndrome.
DOI: 10.1016/j.xcrm.2026.102932

Gene/Genome Editing in Cardiovascular Biology and Disease. (from Cardiology/gene therapy)
Verma Tushar; Singh Ravi Pratap; Chaudhary Mahima; Sharma Pramod Kumar; Kumar Dh — Current gene therapy 2026
Score: 3/10 | Pathways: prime-editing, gene-therapy-delivery

This is a general cardiovascular gene-editing review with no connection to SAMHD1, interferon-mitochondrial mechanisms, or myeloid/immune cell editing relevant to the family syndrome.
DOI: 10.2174/0115665232453929260206091608

Mitochondrial Communication Networks in the Bone Microenvironment: From the Maintenance of Homeostasis to Translational Interventions for Bone Diseases. (from Orthopedics/bone biology)
Wang Wentao; Wang Kun; Wang Wenjing; Mu Xuan; Cheng Zhiquan — 2026
Score: 3/10 | Pathways: cGAS-STING, other

Bone microenvironment mitochondrial transfer review touches cGAS-STING/mtDNA release but is focused on osteoporosis/osteoarthritis biology largely tangential to SAMHD1 interferonopathy mechanism.
DOI: 10.1007/s12015-026-11190-w

An Insight into the cGAS-STING Pathway Modulation by Metal Complexes to Initiate Immunogenic Cell Death in Cancer. (from medicinal chemistry/oncology)
Shilpendu Ghosh; Sujato Mukherjee; Arindam Mukherjee — Journal of medicinal chemistry 2026
Score: 3/10 | Pathways: cGAS-STING, treatment-target

Discusses cGAS-STING pathway modulation via metal complexes for cancer immunotherapy, mechanistically relevant to Loop A but focused on oncology drug design rather than SAMHD1 or the family syndrome.
DOI: 10.1021/acs.jmedchem.6c00727

Caloric restriction enhances radiosensitivity of colorectal tumors through the cGAS-STING pathway activation. (from Oncology/radiation biology)
Li-Li Zhang; Li-Qiang Qin; Li Ding; Wenyue Shan; Yu Zhao — Cancer & metabolism 2026
Score: 3/10 | Pathways: cGAS-STING

This paper studies cGAS-STING pathway activation via caloric restriction to enhance radiosensitivity in colorectal cancer, sharing a core pathway but in an oncology/radiotherapy context unrelated to SAMHD1 dysfunction, mitochondrial dNTP dysregulation, or the interferonopathy syndrome described.
DOI: 10.1186/s40170-026-00449-y

From convergence to an iterative Optimization-Circumvention-Collapse framework in CRISPR bioengineering (from bioengineering/education)
Federico Filippone-Thaulero — Journal of High School Science 2026
Score: 3/10 | Pathways: prime-editing, gene-therapy-delivery

General theoretical review of CRISPR/base/prime editing trade-offs from a high school science journal, with no immune/myeloid cell specificity or SAMHD1 relevance beyond generic gene-editing correction strategy context.
DOI: 10.64336/001c.165176

Pathway Coverage This Week

  • treatment-target: 21 papers
  • cGAS-STING: 18 papers
  • clinical-phenotype: 9 papers
  • JAK-STAT: 6 papers
  • gene-therapy-delivery: 6 papers
  • prime-editing: 5 papers
  • other: 4 papers
  • NLRP3: 4 papers
  • AGS-spectrum: 3 papers
  • NF-kB-IKK: 3 papers
  • ISG15-mitophagy: 2 papers
  • mito-ROS-NF-kB: 2 papers
  • urate-NLRP3: 2 papers
  • POLG-mtDNA: 1 papers
  • VDAC1: 1 papers
  • pregnancy-fetal: 1 papers

SAMHD1 Research Digest — 2026-07-19

Generated by samhd1_monitor | Model: claude-sonnet-5

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

🟡 Medium Relevance (Score 5–6)

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

Chirality-dependent toxicity decoupling: Discovery of a resibufogenin-based L-configured STING inhibitor with superior therapeutic profile for ulcerative colitis. (from medicinal chemistry/gastroenterology (ulcerative colitis drug discovery))
Zhuang Jia-Hua; Zhang Qiu-Heng; Zhou Si-Yu; Wen Yuting; Li Yiming — European journal of medicinal chemistry 2026
Score: 6/10 | Pathways: cGAS-STING, treatment-target

Novel STING inhibitor targeting the STING-TBK1-IRF3-IL-1beta/IL-6/TNF-alpha axis directly relevant to the BLUE loop IFN-I pathway central to this interferonopathy syndrome, though not disease-specific.
DOI: 10.1016/j.ejmech.2026.119146

Biallelic mutations in SUPV3L1 cause a variable leukodystrophy due to impaired mitochondrial degradosome function (from Neurology/neurogenetics (leukodystrophy))
L. Green; Noémie Hamilton; M. Elpidorou; R. Maroofian; Maha S. Zaki — Research Square 2026
Score: 6/10 | Pathways: cGAS-STING, JAK-STAT, AGS-spectrum, clinical-phenotype, other

Describes a distinct mitochondrial nucleic-acid-sensing disorder (mitochondrial dsRNA degradosome dysfunction) converging on type I interferon activation via dysplastic microglia, mechanistically analogous though not identical to the SAMHD1-driven interferonopathy loop (Blue/Red streams).
DOI: 10.21203/rs.3.rs-4356120/v2

Clinical phenotype and laboratory markers in patients affected by haploinsufficiency of A20 (HA20): a case series from two Italian centres (from Rheumatology/pediatric autoinflammatory disease)
Laura De Nardi; Silvia Federici; Eleonora De Martino; Camilla Celani; Martina Gi — RMD Open 2026
Score: 5/10 | Pathways: NF-kB-IKK, clinical-phenotype, AGS-spectrum

A20 (TNFAIP3) haploinsufficiency is a distinct NF-kB-regulatory autoinflammatory disease showing an analogous interferon-signature/NF-kB-driven phenotype with neuropsychiatric comorbidity, offering indirect mechanistic and biomarker parallels to the SAMHD1 interferonopathy-NF-kB axis but no direct SAMHD1 or mitochondrial dNTP data.
DOI: 10.1136/rmdopen-2026-006763

🟢 Low Relevance (Score 3–4)

Potential specialty bridges — skim titles

Low-dose radiotherapy remodels the tumor immune microenvironment via the cGAS–STING pathway: mechanisms, challenges, and combination therapy strategies (from Oncology/radiotherapy)
Yongze He; Xianhu Zeng; Qianyi Liu; Linsen Zhou; Ying Tang — Molecular Cancer 2026
Score: 4/10 | Pathways: cGAS-STING, NF-kB-IKK, treatment-target

This oncology-focused review discusses cGAS-STING and NF-κB activation via radiotherapy-induced DNA damage in tumors, mechanistically overlapping with the Blue loop but in a distinct clinical context (cancer immunotherapy) not directly tied to SAMHD1 or the interferon-mitochondrial syndrome.
DOI: 10.1186/s12943-026-02634-5

Orally delivered Perilla frutescens-derived nanovesicles regulate the gut-kidney biointerface to attenuate hyperuricemia-associated renal injury. (from Nephrology/gut-kidney axis nutraceutical delivery)
Yang Zhuohang; Yang Siqi; Ran Yi; Zhang Tangqing; Zhang Fen — Colloids and surfaces. B, Biointerfaces 2026
Score: 3/10 | Pathways: urate-NLRP3

The paper touches on the GOLD-stream urate-NLRP3 axis via hyperuricemia-induced renal NLRP3 inflammation, but is a nanovesicle/nephrology-nutraceutical study unrelated to SAMHD1 or the broader interferon-mitochondrial mechanism.
DOI: 10.1016/j.colsurfb.2026.115995

Precision prime editing of TP53 mutations for functional tumor suppression in colorectal cancer. (from Oncology/genome engineering)
Azhar Md; Malviya Rishabha; Chandra Phool; Sridhar Sathvik Belagodu; Shareef Jav — Biochemical and biophysical research communications 2026
Score: 3/10 | Pathways: prime-editing

Discusses prime editing technology for TP53 in colorectal cancer, offering only generic technical relevance to gene correction methods rather than SAMHD1 or immune-mitochondrial mechanisms.
DOI: 10.1016/j.bbrc.2026.154311

Oxoisoaporphine Alkaloid Piano-Stool Arene Ruthenium(II) Derivative: A cGAS-STING-Mediated Chemoimmunotherapy Inducer that Acts as a Dual Catalytic Inhibitor of Topoisomerase I/II. (from Medicinal chemistry/oncology drug design)
Liang-Mei Yang; Yuan Lu; Matthew S. Levine; Xueqian Wang; Ya-Qian Shi — Journal of the American Chemical Society 2026
Score: 3/10 | Pathways: cGAS-STING

Describes a ruthenium-based chemotherapeutic that activates cGAS-STING for oncologic immunotherapy, sharing a pathway node but with no connection to SAMHD1, mitochondrial dNTP biology, or the family's clinical phenotypes.
DOI: 10.1021/jacs.6c01872

Pathway Coverage This Week

  • cGAS-STING: 4 papers
  • treatment-target: 2 papers
  • AGS-spectrum: 2 papers
  • clinical-phenotype: 2 papers
  • NF-kB-IKK: 2 papers
  • JAK-STAT: 1 papers
  • other: 1 papers
  • urate-NLRP3: 1 papers
  • prime-editing: 1 papers

Mitochondrial dynamics and metabolic regulation in cellular inflammation: From mechanisms to precision therapeutics

The finding

This is a review article, not a primary research study — it doesn't report new experimental data. Its contribution is synthesis: it pulls together current literature on how mitochondrial fission/fusion balance (largely governed by Drp1-driven fission versus fusion machinery) acts as a "metabolic checkpoint" that licenses NLRP3 inflammasome activation, and it catalogs how oxidized/ribonucleotide-containing mtDNA released from fragmented mitochondria acts as a hyper-immunogenic ligand for cGAS-STING and other cytosolic sensors. It also surveys pharmacological strategies (Drp1 inhibitors, GLP-1 agonists, mitochondrial transplantation, etc.) aimed at this axis across diseases like sepsis, osteoarthritis, and cancer.

Where it fits

For the SAMHD1 A565T model, this review speaks most directly to Arm 2 (mitochondrial) and its intersection with Arm 3 (nucleotide/NLRP3). Two threads are especially relevant: (1) the idea that fragmented mitochondria release mtDNA that is only immunogenic when "fragile" or oxidized — a concept that dovetails with our hypothesis that SAMHD1 dysfunction leads to dNTP-pool imbalance, oxidized mtDNA, and NLRP3 activation; and (2) the general framework linking mitochondrial quality control (fission/fusion, mitophagy) to cGAS-STING signaling, which is the backbone of our VDAC1/ISG15-BECN1 mitophagy-block hypothesis in Arm 2. This review doesn't test our specific nodes (VDAC1, ISG15-BECN1, POLG, MFN1/2, PINK1/Parkin), but it provides independent conceptual support that the mitochondrial-dynamics-to-inflammasome pipeline we're proposing is an active, biologically plausible axis being pursued broadly in the inflammation field.

Caveats

  • This is a narrative review, not new primary data — it synthesizes existing mechanisms rather than testing SAMHD1, ANKIB1, or any A565T-specific node.
  • The diseases discussed (sepsis, neuroinflammation, osteoarthritis, cancer) are not interferonopathies, so applicability to a chronic, low-grade IFN-tone condition like SAMHD1 A565T is inferential, not demonstrated.
  • No heterozygous partial-loss-of-function genetic model is discussed; the fission/fusion-NLRP3 licensing concept is drawn from acute injury/inflammation contexts, which may differ mechanistically from a chronic, dNTP-driven state.

What to watch

The key open question this raises for our model is whether the specific "fragile mtDNA" (oxidized, ribonucleotide-containing) concept described here can be mapped onto SAMHD1 A565T cells experimentally — i.e., does the dNTP excess in Arm 3 actually generate this particular class of hyper-immunogenic mtDNA, and does correcting mitochondrial fission/fusion balance modulate NLRP3 output in patient-relevant cells?

Source: Mitochondrial dynamics and metabolic regulation in cellular inflammation: From mechanisms to precision therapeutics — 2026.

Transition Metal Activation Reframes SAMHD1 Regulation

The finding

Using selective metal enrichment, spectroscopy, biochemical reconstitution, and kinetics, this study redefines which metal cofactors drive SAMHD1's dNTPase activity. The authors report that robust catalysis is preferentially supported by transition metals rather than Mg²⁺, that iron organizes assembly of a dinuclear active site by binding one position and recruiting a second divalent metal, and that manganese can substitute but less efficiently. They further show that mixed-metal active sites retain activity under redox conditions that suppress homodinuclear diiron sites, and that transition metals act as higher-affinity allosteric activators than Mg²⁺ — implicating metal identity in both catalytic and regulatory layers of SAMHD1.

Where it fits

This is a root-cause paper: it speaks to SAMHD1's core dNTPase function, which sits upstream of all three arms of the working model. For a partial loss-of-function variant like p.A565T, the central question is how much residual dNTPase activity remains under physiological conditions — and this work suggests that answer depends on cellular metal flux and redox state, not just protein abundance. That has direct implications for Arm 3 (nucleotide/NLRP3), where dNTP excess is the proposed driver: if iron availability and mixed-metal plasticity buffer catalysis against oxidative inhibition, then local redox/metal conditions could modulate how much dNTP pool control a hypomorphic enzyme retains. The allosteric-activator finding also intersects with SAMHD1's nucleotide-dependent oligomerization, the assembly step a partial LOF variant most plausibly perturbs. This is mechanistic biochemistry that reframes what SAMHD1 needs to work, and by extension what could tip a marginal variant toward or away from functional sufficiency.

Caveats

  • Purified-enzyme biochemistry, not cells. All claims are from reconstituted, in vitro systems; the paper does not measure metal occupancy, dNTP pools, or activity in primary human cells or any disease model.
  • Wild-type SAMHD1, not the A565T variant. The study does not test p.A565T, heterozygosity, or any Aicardi-Goutières-associated mutant; relevance to partial LOF is inferred, not demonstrated.
  • No downstream immune readouts. The metal-plasticity and oxidative-buffering claims are enzymatic; the work makes no measurement of type I IFN, NLRP3/IL-1β, mitochondrial phenotypes, or any Arm 1–3 output.

What to watch

The immediate open question is whether cellular metal availability and redox state actually modulate SAMHD1 dNTPase activity in vivo — and, for our project specifically, whether a hypomorphic variant like p.A565T is more metal- or redox-sensitive than wild-type, which would predict environmental modifiers of dNTP-driven (Arm 3) disease. It is also worth watching whether the iron-dependence intersects mechanistically with the oxidized-mtDNA/NLRP3 axis, since both hinge on oxidative conditions.

Source: Transition Metal Activation Reframes SAMHD1 Regulation — 2026.

SAMHD1 Research Digest — 2026-07-18

Generated by samhd1_monitor | Model: claude-sonnet-5

Summary: 35 papers evaluated | 6 high-relevance (≥7) | 17 medium (5–6) | 12 low (3–4) | 0 scored <3

🔴 High Relevance (Score 7–10)

Auto-added to Zotero (threshold ≥6)

Transition Metal Activation Reframes SAMHD1 Regulation. (from biochemistry/metalloenzyme spectroscopy)
Calderone Logan A; Gizzi Anthony; Pinninti Soumika; Stivers James T; Pandelia Ma — ACS chemical biology 2026
Score: 8/10 | Pathways: dNTPase, treatment-target

This paper directly characterizes the metal cofactor requirements (iron/manganese) for SAMHD1's dNTPase catalytic activity, providing fundamental mechanistic insight into the enzyme whose partial loss-of-function (as in A565T) drives the entire dNTP pool expansion cascade underlying this syndrome.
DOI: 10.1021/acschembio.6c00438

Mitochondrial dynamics and metabolic regulation in cellular inflammation: From mechanisms to precision therapeutics. (from Pharmacology/mitochondrial cell biology)
Park Woo Hyun — Pharmacology & therapeutics 2026
Score: 8/10 | Pathways: NLRP3, cGAS-STING, mito-dNTP-transport, nucleotide-rewiring, treatment-target, VDAC1

Directly engages ox-mtDNA/cGAS-STING/NLRP3 activation via mitochondrial dynamics and explicitly discusses the YME1L-SLC25A33 pyrimidine-imbalance axis, closely paralleling the PNC1/2 nucleotide-carrier mechanism central to the disease model.
DOI: 10.1016/j.pharmthera.2026.109086

MGMT deficiency augments STING-mediated inflammatory responses accompanied by metabolic alterations in macrophages. (from DNA repair biology / cancer genetics)
Kongkavitoon Pornrat; Boonmee Atsadang; Pattarakankul Thitiporn; Wongprom Benjaw — Scientific reports 2026
Score: 7/10 | Pathways: cGAS-STING, NF-kB-IKK, treatment-target, other

Demonstrates that DNA repair deficiency (MGMT) amplifies STING-TBK1-IRF3 signaling and mitochondrial oxidative metabolism in macrophages, directly relevant to the interferon-mitochondrial crosstalk (cGAS-STING/IRF3, mitochondrial respiration, DNA damage) central to the SAMHD1 syndrome's BLUE/RED loops.
DOI: 10.1038/s41598-026-62431-4

The Development of UM-232, a Covalent STING Antagonist. (from Medicinal chemistry/drug discovery)
Barasa Leonard; DeOrsey Leo; O'Reilly Maeve D; Cahill Sara E; Choudhary Shruti — ACS medicinal chemistry letters 2026
Score: 7/10 | Pathways: cGAS-STING, treatment-target

Describes a novel covalent STING antagonist directly targeting the cGAS-STING axis (Loop A) that drives the IFN-I overproduction central to this SAMHD1 haploinsufficiency syndrome, offering potential therapeutic relevance despite no direct SAMHD1 data.
DOI: 10.1021/acsmedchemlett.6c00114

Electroacupuncture alleviates spinal cord injury by regulating M2-like polarization of myeloid cells through CMPK2/NLRP3 inflammasome inhibition. (from Neurology/Rehabilitation (spinal cord injury, acupuncture))
Zhang Kai; Zhang Mengru; Chen Yi; Ni Ziao; Huang Yi — International immunopharmacology 2026
Score: 7/10 | Pathways: NLRP3, mito-dNTp-transport, nucleotide-rewiring, treatment-target

This paper directly implicates CMPK2 as a regulator of NLRP3 inflammasome activation and myeloid polarization, mechanistically connecting the CMPK2-dependent mitochondrial dNTP salvage pathway (a key node in the SAMHD1/PNC1/PNC2 nucleotide-rewiring model) to NLRP3-driven neuroinflammation, offering a non-obvious cross-context validation of the CMPK2/NLRP3 axis relevant to the SAMHD1 haploinsufficiency mechanism.
DOI: 10.1016/j.intimp.2026.116989

Mitochondrial DNA efflux as a potential amplifier of systemic inflammatory network rewiring in heart failure with preserved ejection fraction (from Cardiology)
Xingwei Zhao; Shengyu Huang; Qiuling Li; Yang Yu; Chunxiang Zhang — Frontiers in Immunology 2026
Score: 7/10 | Pathways: cGAS-STING, NLRP3, NF-kB-NLRP3-priming, POLG-mtDNA, clinical-phenotype, treatment-target

Describes mtDNA release activating cGAS-STING/TLR9 and NLRP3 inflammasome as a cross-organ inflammatory amplifier, directly paralleling the BLUE/Loop A and NLRP3 priming mechanisms in the SAMHD1 syndrome model though in a cardiology (HFpEF) context rather than SAMHD1-driven disease.
DOI: 10.3389/fimmu.2026.1866184

🟡 Medium Relevance (Score 5–6)

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

Niflumic acid suppresses NLRP3 inflammasome activation by limiting chloride efflux and mitochondrial ROS production. (from pharmacology/drug repurposing)
Li Yuanhao; Xie Qianqian; Sun Tianyin; Lu Jiwei; Li Mengmeng — Inflammation research : official journal of the European Histamine Research Society ... [et al.] 2026
Score: 6/10 | Pathways: NLRP3, mito-ROS-NF-kB, urate-NLRP3, treatment-target

Paper details a mitochondrial ROS-dependent NLRP3 activation mechanism (via chloride efflux/TMEM16F) and MSU-crystal-driven inflammasome activation, both directly paralleling the GOLD (urate-NLRP3) and mito-ROS-NF-kB routes in the disease model, with NFA representing a potential adjunct NLRP3-targeting therapeutic.
DOI: 10.1007/s00011-026-02328-0

Targeting CCDC90B restores intestinal stem cell function under hyperuricemic stress. (from Gastroenterology/stem cell biology)
Peng Xiuying; Li Moxuan; Zeng Kaixuan; Lv Wantong; Huang Shuai — Stem cell reports 2026
Score: 6/10 | Pathways: NLRP3, urate-NLRP3, treatment-target

Demonstrates the GOLD-stream mechanism (uric acid → mitochondrial ROS → NLRP3 activation) directly, relevant to the family's SAMHD1-driven dGTP/purine catabolism route to inflammasome activation, albeit in intestinal stem cells rather than immune cells.
DOI: 10.1016/j.stemcr.2026.102970

Ring-finger protein 5 protects against diabetic kidney disease by targeting and degrading STING. (from Nephrology/Endocrinology (diabetic kidney disease))
Dong Chunping; Sun Yan; Li Hui; Qiao Yuan; Gao Shan — Pathology, research and practice 2026
Score: 6/10 | Pathways: cGAS-STING, NF-kB-IKK, treatment-target

Demonstrates RNF5-mediated ubiquitin degradation of STING suppressing TBK1/IRF3/NF-kB activation and fibrosis in diabetic kidney disease, offering a plausible downstream therapeutic node for the STING/NF-kB arm of the interferon-mitochondrial syndrome despite being in a different clinical context (nephrology/diabetes).
DOI: 10.1016/j.prp.2026.156618

Targeting MDA5-Mediated Interferon Responses in Type 1 Diabetes: Structural Insights, Mechanism, and Potential Therapeutic Approaches. (from Endocrinology (type 1 diabetes autoimmunity))
Iwaloye Opeoluwa F; Mathews Clayton E; Li Danmeng — Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 2026
Score: 6/10 | Pathways: IRF7-metabolic, NF-kB-IKK, treatment-target, clinical-phenotype

MDA5/IFIH1-driven type I interferon signaling via TBK1/IKKε-IRF and NF-κB converges mechanistically with the SAMHD1 cGAS-STING/NF-κB interferonopathy axis and shares therapeutic logic (JAK/IFN pathway targeting) relevant to autoimmune comorbidities in the family phenotype spectrum.
DOI: 10.1177/10799907261467555

Senegenin mitigates neuroinflammation, pyroptosis, and apoptosis in cerebral ischemia via inhibiting STING and downstream inflammatory pathway. (from neurology/stroke pharmacology)
Chauhan Chandan; Kaundal Ravinder K — European journal of pharmacology 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, NF-kB-IKK, treatment-target

Demonstrates pharmacological STING-TBK1-IRF3 and NF-κB/NLRP3 pathway inhibition reducing pyroptosis/apoptosis in a disease model, directly relevant to the core Loop A/B mechanism though in an unrelated ischemic stroke context rather than SAMHD1-driven interferonopathy.
DOI: 10.1016/j.ejphar.2026.179147

Dietary riboflavin blocks the cGAS-STING pathway to curb hypoxia-induced hepatic inflammation in sub-adult grass carp (Ctenopharyngodon idella). (from veterinary/aquaculture nutrition science)
Zhong Lin; Feng Lin; Wu Pei; Jiang Weidan; Zhang Hongyun — Animal nutrition (Zhongguo xu mu shou yi xue hui) 2026
Score: 6/10 | Pathways: cGAS-STING, VDAC1, NF-kB-IKK, mito-ROS-NF-kB, treatment-target

This fish study demonstrates VDAC1/mtDNA-driven cGAS-STING-TBK1-IRF3/NF-kB (p-P65) activation causing hepatic inflammation under hypoxia, mirroring the BLUE loop and NF-kB crosstalk mechanisms in the SAMHD1 syndrome, with riboflavin as a mitochondrial-protective therapeutic lever relevant to treatment strategies.
DOI: 10.1016/j.aninu.2026.01.012

Reduced myocardial NRG-1/ErbB4 signaling is associated with STING-linked macrophage pyroptotic signaling in sepsis-induced cardiac injury. (from Cardiology/sepsis)
Wei Yanian; Wang QianWen; Shen Cheng; Pan Xia; Kang Wen — International immunopharmacology 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, NF-kB-IKK, treatment-target

This paper demonstrates cGAS-STING-TBK1-IRF3/NF-kB signaling driving macrophage pyroptosis (NLRP3, caspase-1, GSDMD-N) in cardiac injury, directly relevant to the interferon-inflammasome axis and cardiac phenotype seen in the SAMHD1 family, though it lacks any SAMHD1 connection.
DOI: 10.1016/j.intimp.2026.117044

LKB1/ AMPK deficiency aggravates mitochondrial DNA leakage via mTOR-dependent mitophagy damage in liver injury sensitized by trichloroethylene. (from Occupational/environmental toxicology and hepatology)
Zhu Lifu; Wan Chenghuan; Li Zijun; Fan Xuan; Liu Dongsheng — 2026
Score: 6/10 | Pathways: cGAS-STING, mTOR-lysosomal, treatment-target

Demonstrates mitophagy failure leading to mtDNA leakage and cGAS-STING-driven inflammation via LKB1/AMPK/mTOR axis, mechanistically parallel to the mitochondrial-interferon convergence in the SAMHD1 syndrome despite a different toxicological trigger.
DOI: 10.1016/j.cbi.2026.112261

Microglial mitophagy as an immunometabolic checkpoint in alzheimer's disease: linking mitochondrial quality control to neuroinflammation. (from Neurodegeneration/neuroimmunology)
Zou Mingyue; Zhao Tengyu; Wu Weidong; Zhang Jian; Pan Pengyu — 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, ISG15-mitophagy, mTOR-lysosomal, treatment-target

Reviews microglial mitophagy failure driving mtDNA/mtROS-triggered cGAS-STING and NLRP3 activation with TBK1 signaling, mechanistically parallel to the mitochondrial-quality-control/interferon-inflammasome axis central to the SAMHD1 syndrome, though disease context is Alzheimer's rather than SAMHD1.
DOI: 10.1186/s12974-026-03946-5

The MEK inhibitor trametinib incurs mitochondrial injury and induces innate immune responses in the mouse heart (from Cardio-oncology/pharmacology)
Kelsey H. Fisher-Wellman; Richard D. Lutze; Logan G. Kirkland; J. Beak; Mansi Go — Science Advances 2026
Score: 6/10 | Pathways: cGAS-STING, mito-ROS-NF-kB, treatment-target

Demonstrates mitochondrial DNA damage triggering cGAS-STING innate immune activation via mitochondrial dysfunction and ETC impairment, directly paralleling the BLUE/Loop A mechanism in the SAMHD1 syndrome, though in a drug-cardiotoxicity rather than SAMHD1 context.
DOI: 10.1126/sciadv.aeb2695

The mitochondrial logic of inflammaging: how energy imbalance drives fibroblast SASP and tissue-specific aging (from Geroscience/periodontology)
Yu Huan; Qiqi Wang; Rongkaixuan Fang; Yue Sun; Meiya Suo — Frontiers in Immunology 2026
Score: 6/10 | Pathways: cGAS-STING, NLRP3, NF-kB-IKK, mito-ROS-NF-kB, treatment-target

This paper reviews mitochondrial danger signal (mtROS/mtDNA)-driven cGAS-STING/NLRP3/NF-kB convergence in cellular senescence, mechanistically paralleling the SAMHD1 syndrome's Loop A/B and NF-kB crosstalk axes though in a general aging/periodontal context without SAMHD1 involvement.
DOI: 10.3389/fimmu.2026.1881243

How Redox Modulation May Help Prevent Age-Related Decline (from nutrition/geroscience)
M. Amirova — PHYTONutrients 2026
Score: 6/10 | Pathways: NLRP3, cGAS-STING, NF-kB-IKK, NF-kB-NLRP3-priming, mito-ROS-NF-kB, treatment-target

General review of mitochondrial DAMP-driven cGAS-STING/NLRP3/NF-kB inflammaging and NRF2 antioxidant modulation overlaps mechanistically with the IFN-mitochondrial-inflammasome axis but lacks SAMHD1-specific or dNTP pathway data.
DOI: 10.62368/pn.v5i1.71

Biallelic mutations in SUPV3L1 cause a variable leukodystrophy due to impaired mitochondrial degradosome function (from Neurology/leukodystrophy genetics)
L. Green; Noémie Hamilton; M. Elpidorou; R. Maroofian; Maha S. Zaki — Research Square 2026
Score: 6/10 | Pathways: cGAS-STING, AGS-spectrum, clinical-phenotype

Mitochondrial dsRNA degradosome dysfunction driving type I interferon activation via microglia parallels the SAMHD1-driven mitochondrial-to-interferon signaling axis, though it operates through a distinct RNA-sensing (rather than dNTPase/cGAS-mtDNA) mechanism within the broader interferonopathy spectrum.
DOI: 10.21203/rs.3.rs-4356120/v2

A Multi-Center Integrative Cohort Characterizing the Genetic, Clinical, and Transcriptomic Features of ACP5 Deficiency. (from Rheumatology/genetics (skeletal dysplasia and immune dysregulation))
Zhong Shiling; Ma Shuangyue; El Chazli Yasmine; Zheng Jika; Sun Xiangwei — Arthritis & rheumatology (Hoboken, N.J.) 2026
Score: 5/10 | Pathways: JAK-STAT, NF-kB-IKK, AGS-spectrum, clinical-phenotype, treatment-target

ACP5/SPENCDI is a distinct interferonopathy with overlapping type I IFN, NF-κB, and JAK-STAT signaling and JAK inhibitor treatment response, offering mechanistic and therapeutic parallels to the SAMHD1 interferonopathy spectrum despite being a different causal gene.
DOI: 10.1002/art.70279

Leveraging Mitochondria-Endoplasmic Reticulum Functional Interplay With an On-Demand Nanoparticle to Boost mtDNA-Based STING Immunotherapy. (from Oncology/nanomedicine)
Chen Han; Qu Haijing; Pan Yuqing; Cheng Wei; Wu Jie — Advanced materials (Deerfield Beach, Fla.) 2026
Score: 5/10 | Pathways: cGAS-STING, treatment-target

This paper explores mtDNA-driven cGAS-STING activation via a mitochondria-ER nanoparticle system for cancer immunotherapy, which is mechanistically relevant to the BLUE pathway's mtDNA-cGAS-STING axis but oncology-focused rather than SAMHD1-related.
DOI: 10.1002/adma.74146

CD117 epitope-shielded hematopoietic stem cell transplantation with toxin-free conditioning and in vivo selection ameliorates a β-thalassemia model. (from Hematology/gene therapy engineering)
Marone Romina; Lepore Rosalba; Paschoudi Kiriaki; Zuin Jessica; Sinopoli Alessan — bioRxiv : the preprint server for biology 2026
Score: 5/10 | Pathways: prime-editing, gene-therapy-delivery

Uses prime editing to engineer epitope-shielded CD34+ HSPCs for toxin-free conditioning, representing a relevant myeloid/HSC gene correction delivery advance analogous to strategies that could correct SAMHD1 missense variants, though disease context (beta-thalassemia) is unrelated to interferonopathy pathways.
DOI: 10.64898/2026.07.07.736903

Base Editing Hematopoietic Stem/Progenitor Cell Gene Therapy for Treatment of X-Linked Severe Combined Immunodeficiency (from Gene therapy/immunodeficiency)
S. de Ravin; Michelle Ma; Yuzhi Yin; Siyuan Liu; Andrés Zea Vera — Journal of Human Immunity 2026
Score: 5/10 | Pathways: gene-therapy-delivery

Demonstrates base-editing correction of a het/hemizygous immune gene mutation (IL2RG) in HSPCs, relevant as a translational precedent for future SAMHD1 A565T correction strategies but not mechanistically tied to the interferon-mitochondrial-NLRP3 axis.
DOI: 10.70962/pidtc2026abstract.4

🟢 Low Relevance (Score 3–4)

Potential specialty bridges — skim titles

Annual gout flare frequency as a marker of sustained cardiovascular risk: a clinical threshold for risk stratification. (from Rheumatology/Cardiology)
Tung Kuei-Ting; Chen Solomon Chih-Cheng; Lee Chun — Rheumatology (Oxford, England) 2026
Score: 4/10 | Pathways: urate-NLRP3, clinical-phenotype

This clinical epidemiology paper links gout flare frequency to cardiovascular risk via cumulative inflammatory burden, tangentially relevant to the GOLD pathway (dGTP-uric acid-MSU crystal-NLRP3 axis) but does not address SAMHD1, interferon, or mitochondrial mechanisms directly.
DOI: 10.1093/rheumatology/keag370

Approach to the patient with APS-1/APECED. (from Endocrinology)
Webb Taura; Pechacek Joseph; Lionakis Michail S — The Journal of clinical endocrinology and metabolism 2026
Score: 4/10 | Pathways: JAK-STAT, clinical-phenotype, other

APS-1/AIRE is a distinct monogenic autoimmune tolerance disorder with IFN-gamma-driven pathology and JAK inhibitor treatment rationale, offering only loose conceptual parallel (JAKi as interferonopathy therapy) but no direct SAMHD1/cGAS-STING/NLRP3 mechanistic overlap.
DOI: 10.1210/clinem/dgag282

MDA5 and the integrated stress response control sex-specific type 1 diabetes onset in NOD mice. (from Endocrinology/diabetes autoimmunity)
Van Dis Erik; DeGidio Alessandra T; Yao Lara; Winship Damion; Sidrauski Carmela — bioRxiv : the preprint server for biology 2026
Score: 4/10 | Pathways: AGS-spectrum, other

This paper links MDA5/IFIH1 and integrated stress response to autoimmune diabetes in the AGS-adjacent RNA-sensing innate immune context, offering tangential mechanistic overlap (nucleic acid sensing driving type I IFN-like pathology) but no direct SAMHD1, cGAS-STING, NLRP3, or mitochondrial dNTP connection.
DOI: 10.64898/2026.07.02.736190

Compound delivery of eVLPs enhances prime editing for targeted genome engineering and high-throughput screening. (from functional genomics/gene editing technology)
Langley Jethro; Baudrier Lou; Curry Jada; Narta Kiran; Todesco Hayley M — Cell genomics 2026
Score: 4/10 | Pathways: prime-editing, gene-therapy-delivery

General-purpose eVLP/prime-editing methods advance is technically relevant to future SAMHD1 correction strategies but not targeted to immune/myeloid cells or the disease mechanism itself.
DOI: 10.1016/j.xgen.2026.101302

Therapeutic Gene Editing of APOE4 in Sporadic Alzheimer's Disease via Prime Editor 7. (from neurology/gene therapy (Alzheimer's disease))
Kim Yunkyung; Lee Gaeun; An Saemin; Park Hanseul; Kim Hongwon — Advanced science (Weinheim, Baden-Wurttemberg, Germany) 2026
Score: 4/10 | Pathways: prime-editing, gene-therapy-delivery

This paper demonstrates PE7 prime editing technology for allele-specific correction (APOE4→APOE3) in neurons, offering a technical precedent for correcting heterozygous missense variants like SAMHD1 A565T, but is otherwise unrelated to interferonopathy/SAMHD1 biology or immune cell targeting.
DOI: 10.1002/advs.76658

SARS-CoV-2 ORF9b exploits mitochondrial recruitment to TOMM70 for proteasomal protection and tunes inflammatory remodeling during lung infection (from Virology/Structural Biology)
Yining Zhao; Lauriane Kergoat; Guilherme Dias de Melo; F. Larrous; Guillaume Dru — bioRxiv 2026
Score: 4/10 | Pathways: cGAS-STING, other

This paper explores SARS-CoV-2 ORF9b-mitochondrial (TOMM70) interactions and inflammatory remodeling via a Complex IV subunit substitute, touching on mitochondrial-innate immune crosstalk and interferon regulation but without direct SAMHD1, cGAS-STING, or NLRP3 pathway involvement relevant to the described syndrome.
DOI: 10.64898/2026.07.13.738231

Delivery Systems for Therapeutic Genome Editing: Challenges, Innovations, and Future Perspectives (from biomedical engineering/nanomedicine)
Meijia Yang; Yiqiong Song; Ziyang Wang; Ke Chao; Lifeng Li — MedComm 2026
Score: 4/10 | Pathways: prime-editing, gene-therapy-delivery

General review of genome editing delivery platforms with no SAMHD1-specific or immune/myeloid cell targeting focus, only tangentially relevant as background for future gene correction strategies.
DOI: 10.1002/mco2.70791

Proteomics-based characterization of apigenin-mediated anti-inflammatory effects in TNF-α-stimulated ARPE-19 cells. (from Ophthalmology/pharmacology (flavonoid anti-inflammatory research in retinal disease))
Chen Xi; Liao Meilin; Han Ruifang; Gao Juan; Lu Ping — International immunopharmacology 2026
Score: 3/10 | Pathways: NF-kB-IKK, JAK-STAT, ISG15-mitophagy

This paper studies apigenin's suppression of NF-κB/MAPK signaling and interferon-stimulated proteins (STAT1, ISG15, OAS3, IFIT3) in retinal pigment epithelial cells, touching peripheral pathway nodes (NF-κB, ISG15, IFN-related proteins) relevant to the syndrome's mechanism but with no SAMHD1, mitochondrial, or NLRP3 connection and an unrelated ophthalmologic/pharmacologic context.
DOI: 10.1016/j.intimp.2026.117048

Guiqi Baizhu prescription attenuates 5-FU-induced intestinal mucositis by targeting IKKβ to inhibit M1 macrophage polarization. (from Gastroenterology/Traditional Chinese Medicine oncology supportive care)
Zhou Yu-Cen; Li Ya-Ling; Ma Jing; Li Junjie; Si Qi — Chinese medicine 2026
Score: 3/10 | Pathways: NF-kB-IKK

Paper focuses on IKKβ/NF-κB inhibition in a traditional Chinese medicine model of chemotherapy-induced gut mucositis, only tangentially touching the NF-κB-IKK axis without connection to SAMHD1, interferonopathy, or mitochondrial mechanisms.
DOI: 10.1186/s13020-026-01406-z

Nanoengineering Systems for Gene Therapy: Mechanisms, Modalities, and Future Directions. (from nanotechnology/bioengineering)
Mais Raheem; Kumar Ayush; Ahmetaj Armand; Burgos-Crespo Gaby; Sanchez Mary Marga — International journal of molecular sciences 2026
Score: 3/10 | Pathways: gene-therapy-delivery, prime-editing

General review of nanomaterial delivery platforms for CRISPR/base/prime editing with no SAMHD1, immune cell, or mitochondrial-interferon pathway specificity.
DOI: 10.3390/ijms27135988

Intelligent metal-integrated hydrogels orchestrate pyroptosis and cGAS-STING for potentiated treatment of colorectal cancer peritoneal metastasis. (from Oncology/biomaterials drug delivery)
Zhang Lin-Zhu; Si Liang-Wei; Xu Hui; Xiong Fei; Qin Juan — 2026
Score: 3/10 | Pathways: cGAS-STING, other

Describes cGAS-STING activation via mtDNA/pyroptosis in a cancer-therapeutic (hydrogel/cobalt) context unrelated to SAMHD1 mechanism or family phenotypes, though it touches the same signaling node.
DOI: 10.1016/j.jconrel.2026.115184

Orchestrating the gut microbiota–mitochondrial–immune axis in gynecological diseases: mechanisms and dual-targeting therapeutic strategies (from Gynecology/Reproductive Health)
Haixia Tang; Yiting Zhang; Yanting Wang; Ze Zhou; Rong Sun — Frontiers in Reproductive Health 2026
Score: 3/10 | Pathways: cGAS-STING, NLRP3, other

This review covers gut microbiota-mitochondria-immune crosstalk (cGAS-STING/NLRP3, mtDNA, mitophagy) in gynecological disease but is not connected to SAMHD1, dNTP metabolism, or the family phenotype spectrum.
DOI: 10.3389/frph.2026.1845581

Pathway Coverage This Week

  • treatment-target: 20 papers
  • cGAS-STING: 18 papers
  • NLRP3: 11 papers
  • NF-kB-IKK: 11 papers
  • other: 6 papers
  • clinical-phenotype: 6 papers
  • gene-therapy-delivery: 6 papers
  • mito-ROS-NF-kB: 5 papers
  • prime-editing: 5 papers
  • urate-NLRP3: 3 papers
  • AGS-spectrum: 3 papers
  • JAK-STAT: 3 papers
  • nucleotide-rewiring: 2 papers
  • VDAC1: 2 papers
  • NF-kB-NLRP3-priming: 2 papers
  • mTOR-lysosomal: 2 papers
  • ISG15-mitophagy: 2 papers
  • dNTPase: 1 papers
  • mito-dNTP-transport: 1 papers
  • mito-dNTp-transport: 1 papers
  • POLG-mtDNA: 1 papers
  • IRF7-metabolic: 1 papers

Mitochondrial DNA and Mitochondrial-Derived Vesicles as Immunometabolic Modulators of Innate Immunosurveillance through Control of the Mitochondrial Permeability Transition Pore

The finding

This is a mechanistic review rather than a primary experimental study. It synthesizes existing literature into a framework in which the mitochondrial permeability transition pore (mPTP) — a Ca²⁺- and ROS-sensitive channel — is a decisive gatekeeper for the release of oxidized mtDNA. The authors argue that sustained mPTP opening drives mitochondrial depolarization, structural collapse, and escape of mtDNA that then engages cGAS–STING, the NLRP3 inflammasome, and TLR9. In parallel, they position mitochondrial quality control (mitophagy and mitochondrial-derived vesicles, MDVs) as the counterweight that determines whether mitochondrial stress resolves adaptively or converts into sterile inflammation.

Where it fits

This framework speaks directly to ARM 2 (mitochondrial) and ARM 3 (nucleotide/NLRP3), and touches the mtDNA-sensing entry point of ARM 1. For SAMHD1 A565T, the model's central prediction is that mtDNA release is not a single event but a balance between mPTP-dependent rupture and MDV/mitophagy-mediated cargo removal. That is relevant because our working model already posits an ISG15–BECN1 block on mitophagy (ARM 2) and oxidized-mtDNA-driven NLRP3 activation (ARM 3). This review supplies a candidate upstream valve — the mPTP — that could sit between VDAC1 destabilization and mtDNA escape, and it introduces MDVs as an alternative clearance route that may partly compensate when mitophagy is impaired. If correct, it hints at why ARM 2/ARM 3 could be JAK-resistant: the mtDNA release step is governed by mitochondrial channel and clearance biology, not JAK-STAT signaling.

Caveats

  • This is a synthesis, not new data. It proposes an integrated mPTP–mtDNA–MDV axis but does not itself demonstrate this axis in any specific disease model, and nothing here involves SAMHD1, A565T, or partial/heterozygous loss of function.
  • Context-dependence is explicit and unresolved. The authors state MDVs may either limit or promote inflammation depending on cargo and cell type — so the framework does not predict directionality for any given tissue.
  • No link to VDAC1 or ISG15–BECN1 is established here. The connection between our model's specific nodes and the mPTP is a plausible mapping we are drawing, not a claim the paper makes.

What to watch

The key next question is whether mPTP opening is measurably increased in SAMHD1 A565T cells — and, if so, whether MDV-mediated clearance is intact or itself blocked by the hypothesized ISG15–BECN1 mitophagy defect. Testing mPTP modulators against mtDNA release in primary A565T cells would show whether this valve is a JAK-independent therapeutic entry point for ARMs 2 and 3.

Source: Mitochondrial DNA and Mitochondrial-Derived Vesicles as Immunometabolic Modulators of Innate Immunosurveillance through Control of the Mitochondrial Permeability Transition Pore — Translational Insights 2026.

Recent Insights into Mitochondrial Dysfunction-Driven Cellular Senescence in Chronic Kidney Disease

The finding

This appears to be a review article (title format and "Recent Insights" framing suggest a synthesis piece rather than primary data) surveying how mitochondrial dysfunction contributes to cellular senescence in chronic kidney disease (CKD). No abstract is available for this entry, so we cannot describe specific experiments, model systems, or quantitative results the authors report — only the general topic the title indicates.

Where it fits

Taken at face value, this paper sits closest to ARM 2 (mitochondrial) of the SAMHD1 A565T model, which posits that VDAC1 destabilization and mtDNA release, compounded by an ISG15-BECN1 block on mitophagy, drive a partly JAK-resistant inflammatory phenotype. Reviews on mitochondrial dysfunction and senescence in CKD typically touch on the same molecular vocabulary relevant to Arm 2 — mitophagy machinery (PINK1/Parkin), mitochondrial fusion/fission (MFN1/2), mtDNA integrity (POLG), and downstream senescence-associated secretory phenotypes that overlap with chronic low-grade interferon/inflammatory signaling. If the review discusses mtDNA-driven senescence pathways in kidney cells, it could offer conceptual scaffolding for how chronic mitochondrial stress (as hypothesized in Arm 2) might translate into organ-specific pathology over time — CKD being a plausible, though currently unconfirmed, comorbidity of interest in interferonopathy models. We flag this as a topical/conceptual connection, not an established link to SAMHD1 biology.

Caveats

  • No abstract or results are available to us, so nothing here should be read as a specific finding "shown" by the paper — the connection to SAMHD1 A565T is purely thematic overlap in molecular pathways, inferred from the title alone.
  • This looks to be a review, not primary research; it likely synthesizes existing literature on CKD and senescence rather than generating new mechanistic data.
  • Kidney disease context is not part of the current SAMHD1 A565T working model — there is no established evidence tying this variant to CKD, senescence, or the specific pathways this review may cover.

What to watch

Once full text is accessible, the key question is whether the mitochondrial-senescence mechanisms it reviews (mtDNA release, mitophagy failure, POLG/PINK1-Parkin dysfunction) are described in ways that could generate testable hypotheses for Arm 2 of the SAMHD1 A565T model — partic

Source: Recent Insights into Mitochondrial Dysfunction-Driven Cellular Senescence in Chronic Kidney Disease — BIOCELL 2026.

SAMHD1 Research Digest — 2026-07-13

Generated by samhd1_monitor | Model: claude-sonnet-5

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

🔴 High Relevance (Score 7–10)

Auto-added to Zotero (threshold ≥6)

Mitochondrial DNA and Mitochondrial-Derived Vesicles as Immunometabolic Modulators of Innate Immunosurveillance through Control of the Mitochondrial Permeability Transition Pore (from Mitochondrial cell biology / immunometabolism)
Patrycja Anna Glogowski; S. Nesci; Antonia Cugliari; F. Trombetti; M. Fabbri — Translational Insights 2026
Score: 8/10 | Pathways: cGAS-STING, NLRP3, VDAC1, NF-kB-IKK, POLG-mtDNA, treatment-target

This paper details the mPTP-mtDNA-NLRP3/cGAS-STING axis and mitochondrial quality control (mitophagy/MDVs) that directly parallels the BLUE/PURPLE mechanism loops (VDAC1-mediated mtDNA escape, ox-mtDNA, NLRP3 activation) central to the SAMHD1 A565T pathophysiology, though it does not mention SAMHD1 itself.
DOI: 10.53941/ti.2026.100010

🟡 Medium Relevance (Score 5–6)

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

METTL5-mediated rRNA modification controls prostate cancer progression through the IRF7/DNA2 axis and mitophagy regulation. (from Oncology (prostate cancer molecular biology))
Yang Ruifeng; Ge Qintao; Wu Fengyao; Long Manmei; Li Bingyu — Oncogene 2026
Score: 6/10 | Pathways: IRF7-metabolic, POLG-mtDNA, BIK-cancer, clinical-phenotype

This paper links IRF7 (a core interferon pathway transcription factor also relevant to SAMHD1 biology) to mitochondrial DNA maintenance (via DNA2) and mitophagy in prostate cancer, a phenotype tracked in the SAMHD1 family, though the mechanism (rRNA m6A/METTL5) is distinct from SAMHD1 dNTPase pathways.
DOI: 10.1038/s41388-026-03867-w

Design and Synthesis of Novel Isoflavene TANK-Binding Kinase 1 Inhibitors With Anti-Inflammatory Activity. (from medicinal chemistry/drug design)
Falasca Valerio; Jayasekara W Samantha N; Nardo Dominic De; Wenholz Daniel S; Ga — ChemMedChem 2026
Score: 6/10 | Pathways: NF-kB-IKK, treatment-target

TBK1 inhibitors targeting NF-κB and type I IFN signaling are directly relevant to the IKKε/TBK1 non-canonical NF-κB and IRF3/IFN-I axis described in the disease mechanism, offering a potential therapeutic strategy for the interferonopathy component.
DOI: 10.1002/cmdc.70376

Successful salvage treatment with baricitinib for macrophage activation syndrome complicating adult-onset Still's disease during interleukin-6 inhibition: a case report and literature review. (from Rheumatology)
Nishisaka Kazuma; Ueda Yo; Shirasugi Iku; Yamada Hirotaka; Okano Takaichi — Modern rheumatology case reports 2026
Score: 5/10 | Pathways: JAK-STAT, treatment-target, clinical-phenotype

Baricitinib (JAK1/2 inhibitor) treating hyperinflammatory macrophage activation syndrome via IL-6/IFN-gamma/GM-CSF overlaps with the IFN-I/JAK-STAT axis and NLRP3-driven hyperinflammation central to the SAMHD1 model, with direct treatment-target relevance despite lacking SAMHD1 linkage.
DOI: 10.1093/mrcr/rxag072

CD117 epitope-shielded hematopoietic stem cell transplantation with toxin-free conditioning and in vivo selection ameliorates a β-thalassemia model (from Hematology/gene therapy engineering)
Romina Marone; Rosalba Lepore; K. Paschoudi; Jessica Zuin; A. Sinopoli — bioRxiv 2026
Score: 5/10 | Pathways: prime-editing, gene-therapy-delivery

Uses prime editing on CD34+ HSPCs to engineer epitope resistance for toxin-free conditioning, relevant as a myeloid/HSC gene-editing delivery advance analogous to future correction strategies for a het missense variant like SAMHD1 A565T, though not disease-specific.
DOI: 10.64898/2026.07.07.736903

🟢 Low Relevance (Score 3–4)

Potential specialty bridges — skim titles

Organ-resolved endothelial regulatory programs link aging and metabolic overload to vascular immune remodeling (from Vascular biology/aging endothelial genomics)
Masataka Yokoyama; A. Nakayama; Yuki Taki; Mingyang Chen; Yingbo Gong — bioRxiv 2026
Score: 4/10 | Pathways: JAK-STAT, IRF7-metabolic, other

This paper describes an IRF/STAT-centered type I IFN endothelial aging program and metabolic vascular remodeling, tangentially echoing IFN-I/JAK-STAT themes but without SAMHD1, NLRP3, cGAS-STING, or mitochondrial dNTP mechanisms central to the disease profile.
DOI: 10.64898/2026.07.02.736039

Pathway Coverage This Week

  • treatment-target: 3 papers
  • NF-kB-IKK: 2 papers
  • POLG-mtDNA: 2 papers
  • IRF7-metabolic: 2 papers
  • clinical-phenotype: 2 papers
  • JAK-STAT: 2 papers
  • cGAS-STING: 1 papers
  • NLRP3: 1 papers
  • VDAC1: 1 papers
  • BIK-cancer: 1 papers
  • prime-editing: 1 papers
  • gene-therapy-delivery: 1 papers
  • other: 1 papers

SAMHD1 Research Digest — 2026-07-12

Generated by samhd1_monitor | Model: claude-sonnet-5

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

🟡 Medium Relevance (Score 5–6)

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

Abscisic acid ameliorates inflammation-related diseases by inhibiting NLRP3 inflammasome activation. (from pharmacology/natural product chemistry)
Jiao Chenyang; Jia Lulu; Liu Qian; Zhang Weihang; Zhang Wei — International immunopharmacology 2026
Score: 6/10 | Pathways: NLRP3, urate-NLRP3, mTOR-lysosomal, treatment-target

This paper identifies a novel NLRP3 inhibitor (ABA/PDZD8-lysosomal axis) validated in MSU-induced gouty arthritis, directly relevant to the GOLD stream (dGTP→uric acid→MSU crystals→NLRP3) and offers a potential therapeutic strategy for NLRP3 hyperactivation in the syndrome.
DOI: 10.1016/j.intimp.2026.117119

ADAR1 loss-of-function variants altering RNA editing define a new interferon-dependent psoriasis subtype. (from Dermatology/Rheumatology (psoriasis, psoriatic arthritis))
Assan Florence; Tragin Margot; Marella Sahiti; Lipecka Joanna; Roger Kévin — The Journal of experimental medicine 2026
Score: 6/10 | Pathways: JAK-STAT, treatment-target, clinical-phenotype, AGS-spectrum

Monogenic ADAR1 loss-of-function causing constitutive type I IFN signature and inflammatory disease (psoriasis) mirrors the interferonopathy mechanism central to SAMHD1 A565T pathology, and JAK inhibitor (upadacitinib) responsiveness directly parallels proposed treatment strategies for the family syndrome.
DOI: 10.1084/jem.20260054

A micropeptide encoded by the lncRNA USP30-AS1 promotes tumor growth by attenuating cGAS-STING-type I IFN signaling in macrophages. (from Oncology/tumor immunology)
Wang Xingwen; Zhang Yi; Ma Jiangwen; Lin Qingyu; Wang Zhenghang — Nature cancer 2026
Score: 6/10 | Pathways: cGAS-STING, treatment-target

This paper details a novel negative-feedback mechanism (UEIS-TBK1 condensates) directly within the cGAS-STING-TBK1-type I IFN axis in macrophages, a core pathway implicated in the SAMHD1 interferonopathy syndrome, though its focus on tumor immunology rather than SAMHD1/mitochondrial dysfunction limits direct relevance.
DOI: 10.1038/s43018-026-01195-2

STING-associated metabolic changes engage AMPK to amplify interferon signaling in Listeria-infected macrophages. (from Microbiology/infectious disease immunometabolism)
Chen Shukun; Wang Xiao; Duan Zhuoyu; Wang Min; Qu Xiaoya — Biochimica et biophysica acta. Molecular cell research 2026
Score: 6/10 | Pathways: cGAS-STING, treatment-target, other

Demonstrates STING-driven metabolic reprogramming (glycolysis/AMPK/TBK1) amplifying type I IFN signaling, directly relevant to the STING/IFN-I axis (Loop A) though in a bacterial infection context rather than SAMHD1-driven cGAS-STING activation.
DOI: 10.1016/j.bbamcr.2026.120172

ISG15 At the Crossroads of Innate Immunity and Host Survival in Response to Typhoid Toxin. (from microbiology/infectious disease (Salmonella typhoid toxin biology))
Valenzuela Camila; Enninga Jost — Molecular microbiology 2026
Score: 6/10 | Pathways: cGAS-STING, ISG15-mitophagy, treatment-target

Describes a STING-TBK1-dependent, ISGylation-independent free ISG15 pathway triggered by cytosolic DNA sensing that promotes cell survival, mechanistically parallel to the BLUE/RED axes in the SAMHD1 syndrome even though the trigger is bacterial genotoxin rather than mtDNA leakage.
DOI: 10.1111/mmi.70075

Recent Insights into Mitochondrial Dysfunction-Driven Cellular Senescence in Chronic Kidney Disease (from Nephrology)
Ziyi Guo; Zhenkai Wang; Zixuan Song; Tian Wang; Jingai Fang — BIOCELL 2026
Score: 5/10 | Pathways: NLRP3, cGAS-STING, POLG-mtDNA, treatment-target

Discusses mitochondrial dysfunction driving cGAS-STING/NLRP3-mediated senescence and SASP, mechanistically overlapping with the interferon-mitochondrial pathways in the SAMHD1 syndrome but in a CKD context without any SAMHD1 or direct genetic linkage.
DOI: 10.32604/biocell.2026.083188

🟢 Low Relevance (Score 3–4)

Potential specialty bridges — skim titles

Mitoxyperilysis related signature predicts prognosis innate immune remodeling and myeloid enriched tumor microenvironment states in breast cancer (from oncology)
Li Zhen; Yang Menglei; Li Yongfei — preprint (preprint) 2026
Score: 4/10 | Pathways: NLRP3, cGAS-STING, other

This breast cancer bioinformatics paper touches NLRP3/cGAS-STING and mitochondrial lytic cell death but is oncology-context focused on tumor prognosis signatures rather than SAMHD1 mechanism or family phenotype relevance.
DOI: 10.21203/rs.3.rs-9963383/v1

p38 MAP kinase senses short-chain fatty acids to attenuate Toll-like receptor signaling and intestinal inflammation. (from Gastroenterology/microbiome metabolism)
Wu Qingang; Shi Rongkai; Xiao Liwei; He Xuxiao; Chen Zhuoneng — Science advances 2026
Score: 3/10 | Pathways: cGAS-STING, NF-kB-IKK, other

This paper describes SCFA-mediated suppression of TLR/TBK1-IRF3 signaling in intestinal inflammation, sharing the TBK1-IRF3 node with the BLUE loop but is otherwise unrelated to SAMHD1 or the core interferon-mitochondrial mechanism.
DOI: 10.1126/sciadv.aef1419

TANK potentiates antiviral innate immunity by recruiting deubiquitinase USP46 to activate IKKε. (from Fish virology/comparative immunology)
Li Zhenghao; Yang Can; Shu Juanjuan; Wang Jiaxin; Wang Xinyu — PLoS pathogens 2026
Score: 3/10 | Pathways: NF-kB-IKK

This paper describes IKKε regulation by TANK/USP46 in fish antiviral immunity, a tangential non-mammalian model with only distant relevance to the IKKε/IRF3/NF-kB axis implicated in the SAMHD1 syndrome.
DOI: 10.1371/journal.ppat.1014412

Pathway Coverage This Week

  • treatment-target: 6 papers
  • cGAS-STING: 6 papers
  • NLRP3: 3 papers
  • other: 3 papers
  • NF-kB-IKK: 2 papers
  • urate-NLRP3: 1 papers
  • mTOR-lysosomal: 1 papers
  • JAK-STAT: 1 papers
  • clinical-phenotype: 1 papers
  • AGS-spectrum: 1 papers
  • ISG15-mitophagy: 1 papers
  • POLG-mtDNA: 1 papers