GSDME Deficiency Suppresses ER Stress-Induced Autophagic Cell Death via mTOR/S6K1 Activation in Hepatobiliary Carcinomas

Endoplasmic reticulum (ER) stress activation triggers programmed cell death through coordinated Autophagy and Apoptosis pathways. Although Gasdermin E (GSDME) is established as a Pyroptosis executor and tumor suppressor, its regulatory role in ER stress-mediated Autophagy remains unknown. In this study, we identify GSDME as a critical modulator of autophagic flux during ER stress-induced cell death. Using the novel GRP78 inhibitor YUM70, we demonstrate potent antitumor activity in cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) models through ER stress-mediated Autophagy, characterized by elevated LC3-II/I ratios and Caspase-3/PARP activation. Paradoxically, YUM70 treatment induced dose-dependent GSDME downregulation across hepatobiliary Cancer cells. Genetic ablation of GSDME significantly attenuated YUM70-induced autophagic death via reactivation of the mTOR/S6K1 signaling axis. Mechanistically, GSDME maintains autophagic flux by suppressing mTOR-mediated lysosomal biogenesis during ER stress. These findings unveil a non-canonical function of GSDME as an Autophagy rheostat and provide mechanistic insights into chemotherapy resistance in GRP78-targeted therapies. Our work establishes GSDME expression status as a predictive biomarker and therapeutic target for hepatobiliary malignancies undergoing ER stress modulation.