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However, therapeutic resistance to TMZ frequently arises, partly attributed to autophagy, as demonstrated by analysis of clinical glioblastoma specimens. Through screening of mulberry metabolites, a bioactive small molecule, Sanggenol L (SL) is identified, which inhibits glioblastoma growth and blocks autophagy flux, thereby markedly enhancing TMZ chemosensitivity when delivered via a liposome\u2010based system. Mechanistically, SL is found to suppress mitophagy by promoting ubiquitin\u2010mediated proteasomal degradation of OPTN. Moreover, the first evidence that SL upregulates TRIM16 expression is presented, which acts as an E3 ubiquitin ligase for OPTN degradation in glioblastoma. TRIM16 depletion or OPTN overexpression partially abrogated SL\u2010induced suppression of autophagy and apoptosis in GBM cells. Collectively, these findings suggest that SL enhances TMZ sensitivity by disrupting autophagy and inducing apoptosis through TRIM16\u2010mediated OPTN degradation.<\/jats:p>","DOI":"10.1002\/advs.202502915","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T12:47:49Z","timestamp":1758718069000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Sanggenol L Enhances Temozolomide Drug Sensitivity by Inhibiting Mitophagy and Inducing Apoptosis Through the Regulation of the TRIM16\u2010OPTN Axis in Glioblastoma"],"prefix":"10.1002","volume":"12","author":[{"given":"Hongbo","family":"Chang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Resource Insects Medical Research Institute Southwest University  Chongqing 400715 China"},{"name":"Jinfeng Laboratory  Chongqing 401329 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