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In this study, we found that Triosephosphate isomerase 1 (TPI1) plays a crucial role in influencing gemcitabine (Gem) resistance in BCa. TPI1 is significantly upregulated in Gem-resistant BCa tissues, and the knockdown of TPI1 markedly increases Gem sensitivity and chemotherapy-induced apoptosis both in vivo and in vitro. Meanwhile, the same was validated in Gem-resistant strains. Mechanistically, transcriptome sequencing and transmission electron microscopy, among others, revealed that TPI1 promoted Gem-associated autophagy. Furthermore, mass spectrometry and co-immunoprecipitation assays demonstrated that TPI1 directly binds to the BH3 domain of Beclin-1. This interaction competitively disrupts the binding between Bcl-2 and Beclin-1, thereby relieving Bcl-2-mediated inhibition of Beclin-1. Furthermore, the interaction between TPI1 and Beclin-1 promotes the formation of PIK3C3-C1, which in turn enhances the interaction between PIK3C3-C1 and the ULK1 complex, thereby increasing the phosphorylation of Beclin-1 at Ser15. In addition, TPI1 also enhanced mitochondrial autophagy induced by Gem in BCa cells and tissues. Importantly, a transcription factor, c-Myc, that regulates TPI1 expression was also identified, and dual luciferase and Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) analysis showed that c-Myc binds primarily to the promoter region of TPI1. Our results suggest that TPI1 plays an important role in regulating the formation of autophagic complexes, and that promoting autophagy significantly increased Gem resistance in BCa.<\/jats:p>","DOI":"10.1038\/s41419-025-08368-4","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T16:22:29Z","timestamp":1766420549000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["TPI1 enhances gemcitabine resistance in bladder cancer by promoting autophagy through activating Beclin-1"],"prefix":"10.1038","volume":"16","author":[{"given":"Chenyang","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunpeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanhui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1151-5942","authenticated-orcid":false,"given":"Li","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,22]]},"reference":[{"key":"8368_CR1","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1038\/s41572-023-00468-9","volume":"9","author":"L Dyrskj\u00f8t","year":"2023","unstructured":"Dyrskj\u00f8t L, Hansel DE, Efstathiou JA, Knowles MA, Galsky MD, Teoh J, et al. 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