PGC-1α mediates ER stress-driven apoptotic signaling during gemfibrozil treatment in glioblastoma.

Glioblastoma (GBM) is a highly aggressive and therapy-resistant brain tumor. In our earlier study, we demonstrated that the antihyperlipidemic drug Gemfibrozil, when repurposed, exerts strong cytotoxic effects on GBM cells by modulating autophagy. In the present study, we further investigated the complex interplay among key homeostatic pathways, specifically autophagy, endoplasmic reticulum (ER) stress, and calcium signalling, following Gemfibrozil exposure in the context of GBM progression and treatment resistance. Our findings reveal that Gemfibrozil-induced inhibition of autophagy triggers the unfolded protein response (UPR), leading to activation of ER stress pathways, as evidenced by altered expression of canonical markers, including IRE1α, PERK, and CHOP. Notably, CHOP silencing reduced levels of cleaved Caspase-3 and Caspase-9, confirming the involvement of ER stress-mediated apoptosis following disruption of autophagy. Moreover, the induction of ER stress and inhibition of autophagy were accompanied by disturbances in calcium homeostasis, demonstrated by reduced expression of the calcium-binding proteins Calmodulin and Calreticulin. This imbalance resulted in mitochondrial calcium overload, loss of mitochondrial membrane potential, and elevated reactive oxygen species (ROS) production, ultimately culminating in caspase activation and cell death. Mechanistically, PGC-1α emerged as a key regulator of Gemfibrozil-mediated anti-tumor activity. Collectively, our findings uncover a critical molecular cascade involving suppression of autophagy, induction of ER stress, calcium dysregulation, mitochondrial dysfunction, and oxidative stress that drives GBM cell death. These insights not only highlight Gemfibrozil as a potential therapeutic agent but also emphasize the importance of targeting homeostatic vulnerabilities in GBM.