ReviewFrontiers in medicine2026
Necroptosis-senescence crosstalk in tubulointerstitial fibrosis: the mtDNA-cGAS-STING-PFKFB3 axis as a metabolic bridge.
Review in Frontiers in medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Authors and funding
7 authors.
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Abstract
Background: Chronic kidney disease progresses irreversibly toward tubulointerstitial fibrosis. Although renin-angiotensin system inhibitors and sodium-glucose cotransporter 2 inhibitors slow progression, they cannot block or reverse fibrosis. Recent work shows that necroptosis and cellular senescence in tubular epithelial cells are not independent events; they form a dynamically evolving continuum through the mitochondrial DNA-cyclic GMP-AMP synthase-stimulator of interferon genes-interferon regulatory factor 3-6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3-glycolysis axis. Methods: We conducted a narrative review of peer-reviewed literature at the intersection of necroptosis, cellular senescence, and renal tubulointerstitial fibrosis. Systematic searches of PubMed/MEDLINE, Web of Science, and Embase were performed on 15 July 2026 using Medical Subject Headings terms and free-text keywords; evidence was classified using a pragmatic taxonomy ( Results: Necroptotic tubular epithelial cell death releases mitochondrial DNA that activates cyclic GMP-AMP synthase-stimulator of interferon genes-interferon regulatory factor 3-dependent 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 transcription, driving glycolytic reprogramming that sustains and amplifies the senescence-associated secretory phenotype through histone H4 lysine 12 lactylation. Senescence-associated secretory phenotype factors activate interstitial fibroblasts and reciprocally prime adjacent tubular epithelial cells for necroptosis, creating a self-amplifying loop. Existing targeted strategies-inhibitors of receptor-interacting serine/threonine-protein kinase 1, senolytics, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 blockers, and multi-target traditional Chinese medicine-show preclinical efficacy but face translation barriers arising from target selectivity, biomarker absence, and ill-defined therapeutic windows. Conclusion: Future antifibrotic strategies should shift from single-molecule inhibition to network remodeling, using chronology-based combination therapy tailored to disease stage and guided by dynamic biomarkers.
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