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Using stress\u2010 and replication\u2010induced senescent cells, we demonstrate that Celastrol selectively triggers intrinsic apoptosis\u2014evidenced by viability assays, Annexin V\/PI, cleaved caspase\u20103 and blockade by the pan\u2010caspase inhibitor Z\u2010VAD\u2010FMK\u2014while ferroptosis is excluded by specific inhibitors. Proteomic, co\u2010immunoprecipitation\/mass spectrometry, biolayer interferometry, ubiquitination assays and RNAi identify Hsc70 as a binding partner; Celastrol disrupts an Hsc70\u2013Bim\u2013CHIP complex, reduces Bim ubiquitination and stabilizes Bim protein, and Bim knockdown attenuates caspase activation and senolysis. In\u00a0vivo, Celastrol reduces intestinal senescence and extends\n                    <jats:italic>Drosophila<\/jats:italic>\n                    median and maximum lifespan, and mitigates bleomycin\u2010 and CCl\u2084\u2010induced pulmonary and hepatic fibrosis in mice with increased cleaved caspase\u20103 in p16\u207a cells. A \u03b2\u2010galactosidase\u2010activated prodrug (CeGal) preserves efficacy, preferentially releases Celastrol in \u03b2\u2010galactosidase\u2010high cells, and markedly reduces systemic toxicity, supporting clinical translation of this targeted senolytic approach.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70220","type":"journal-article","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T01:54:01Z","timestamp":1769392441000},"page":"1472-1494","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Celastrol Targets Hsc70\u2010Bim Interaction as a Novel Senolytic to Extend Lifespan and Mitigate Organ Fibrosis"],"prefix":"10.1002","volume":"40","author":[{"given":"Weitong","family":"Xu","sequence":"first","affiliation":[{"name":"Sichuan University, State Key Laboratory of Biotherapy  Chengdu 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