{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T20:33:03Z","timestamp":1791923583340,"version":"4.3.4"},"reference-count":41,"publisher":"Wiley","issue":"56","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Cellular senescence is a stable cell cycle arrest program with important therapeutic implications in cancer, yet how metabolic perturbations are translated into redox\u2010dependent senescence remains incompletely understood. Here, we identify triosephosphate isomerase 1 (TPI1) as a critical regulator of senescence in clear cell renal cell carcinoma (ccRCC) through a customized CRISPR\u2010Cas9 metabolic screen. TPI1 depletion induces a robust senescence phenotype characterized by mitochondrial redox imbalance, DNA damage, and stable growth arrest. Mechanistically, loss of TPI1 leads to accumulation of dihydroxyacetone phosphate (DHAP), which engages a SARM1\u2010dependent signaling pathway, resulting in increased cyclic ADP\u2010ribose (cADPR) production and intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release. This cADPR\u2010Ca\n                    <jats:sup>2+<\/jats:sup>\n                    axis drives mitochondrial ROS (mtROS) generation, thereby promoting DNA damage and activation of the p53\u2010p21 pathway to enforce senescence. Pharmacological or genetic attenuation of calcium signaling, or mitochondrial ROS partially rescues these phenotypes, indicating that calcium\u2010dependent redox stress is required for senescence induction. Importantly, this metabolic\u2013redox signaling cascade is conserved across multiple cancer types. Collectively, our findings define a previously unrecognized TPI1\u2013SARM1\u2013cADPR\u2013Ca\n                    <jats:sup>2+<\/jats:sup>\n                    axis that links glycolytic metabolite accumulation to mitochondrial redox stress and cellular senescence, highlighting a metabolite\u2010driven redox vulnerability that may be therapeutically exploitable in cancer.\n                  <\/jats:p>","DOI":"10.1002\/advs.76614","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T20:29:21Z","timestamp":1784320161000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["TPI1 Loss Triggers a Metabolite\u2010Driven Mitochondrial Redox Vulnerability via the SARM1\u2013cADPR\u2013Ca\n                    <sup>2+<\/sup>\n                    Axis"],"prefix":"10.1002","volume":"13","author":[{"given":"Chunyu","family":"Liu","sequence":"first","affiliation":[{"name":"Senior Department of 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