Sanggenol L Induces Endoplasmic Reticulum Stress and Triggers Cell Apoptosis in Glioblastoma by Binding to BiP

Morus alba L. (white mulberry) is a medicinal plant whose extracts possess significant anti-tumor potential. Through screening 59 commercially available mulberry-derived compounds, we identified a small molecule, Sanggenol L (SL), which exhibited potent inhibitory effects on glioblastoma while showing minimal toxicity toward normal cells. This study aimed to elucidate the anti-cancer function and underlying mechanism of SL in glioblastoma cells. Experimental results demonstrated that SL induced cytotoxic endoplasmic reticulum (ER) stress, suppressed cell viability, and triggered apoptosis. Mechanistically, LC-MS/MS and CETSA analyses revealed that SL specifically binds to BiP, creating a steric hindrance that blocks its interaction with IRE1α. This leads to excessive dimerization of IRE1α and hyper-activation of the IRE1/CHOP/XBP1s/Bcl-2 pathway, thereby amplifying cytotoxic ER stress and ultimately promoting apoptosis. Furthermore, we found that SL promotes ubiquitination and degradation of MGMT, consequently enhancing the chemosensitivity of glioblastoma to temozolomide.