Sanggenol L Enhances Temozolomide Drug Sensitivity by Inhibiting Mitophagy and Inducing Apoptosis Through the Regulation of the TRIM16‐OPTN Axis in Glioblastoma

Glioblastoma (GBM) is the most aggressive and lethal form of glioma, with current standard-of-care treatments including surgical resection, radiotherapy, and chemotherapy with temozolomide (TMZ). 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-based system. Mechanistically, SL is found to suppress mitophagy by promoting ubiquitin-mediated 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-induced 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-mediated OPTN degradation.