{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:12:56Z","timestamp":1788415976303,"version":"build-2803163510"},"reference-count":75,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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 (\n                      <jats:italic>in vitro<\/jats:italic>\n                      ,\n                      <jats:italic>in vivo<\/jats:italic>\n                      , phase I\/II, and\n                      <jats:italic>post hoc<\/jats:italic>\n                      \/subgroup analyses).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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\u2014inhibitors 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\u2014show preclinical efficacy but face translation barriers arising from target selectivity, biomarker absence, and ill-defined therapeutic windows.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1882589","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:17:47Z","timestamp":1788412667000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Necroptosis\u2013senescence crosstalk in tubulointerstitial fibrosis: the mtDNA\u2013cGAS\u2013STING\u2013PFKFB3 axis as a metabolic bridge"],"prefix":"10.3389","volume":"13","author":[{"given":"Donghui","family":"Wang","sequence":"first","affiliation":[{"name":"Graduate School, Nanjing University of Chinese Medicine","place":["Nanjing, China"]},{"name":"Department of Nephrology, Changzhou Affiliated Hospital of Nanjing University of Chinese Medicine","place":["Changzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxiang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Changzhou Affiliated Hospital of Nanjing University of Chinese Medicine","place":["Changzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Graduate School, Nanjing University of Chinese Medicine","place":["Nanjing, China"]},{"name":"Department of Nephrology, Changzhou Affiliated Hospital of Nanjing University of Chinese Medicine","place":["Changzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenghua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Changzhou Affiliated Hospital of Nanjing University of Chinese Medicine","place":["Changzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Graduate School, Nanjing University of Chinese Medicine","place":["Nanjing, China"]},{"name":"Department of Nephrology, Changzhou Affiliated Hospital of Nanjing University of Chinese Medicine","place":["Changzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuqi","family":"Min","sequence":"additional","affiliation":[{"name":"Graduate School, Nanjing University of Chinese Medicine","place":["Nanjing, China"]},{"name":"Department of Nephrology, Changzhou Affiliated Hospital of Nanjing University of Chinese Medicine","place":["Changzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenju","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Changzhou Affiliated Hospital of Nanjing University of Chinese Medicine","place":["Changzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"697","DOI":"10.34067\/KID.0001972020","article-title":"Janus-faced: Molecular mechanisms and versatile nature of renal 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