BIOM-28. FOSL2 PROMOTES FERROPTOSIS RESISTANCE IN GLIOBLASTOMA

Abstract FOSL2 is a biomarker for mesenchymal subtype of glioblastoma, but its role in the regulation of ferroptosis remains poorly understood. Here we revealed that FOSL2 promotes resistance to ferroptosis in glioblastoma.FOSL2 expression is positively correlated with the pathological grade of glioma and negatively correlated with patient survival. Mechanistically, FOSL2 promotes glioblastoma cell proliferation and migration and confers resistance to TMZ. In vitro and in vivo studies demonstrate that compared to controls, FOSL2-overexpressing GBM cells exhibit upregulation of ferroptosis regulators SLC7A11 and GPX4, downregulation of ACSL4 (a ferroptosis promoter), reduced Fe²⁺ and ROS levels, and increased mitochondrial activity. We further elucidate that FOSL2 enhances GPX4 palmitoylation, thereby stabilizing the protein and conferring resistance to ferroptosis. Additionally, we demonstrated that the combination of the ferroptosis inducer Erastin with TMZ significantly reduces the survival and migration of GBM cells, potentially enhancing Erastin-induced ferroptosis in GBM xenograft models. Transmission electron microscopy (TEM) analysis of the combination therapy group revealed three mitochondrial abnormalities:Cristae thickening, Focal membrane dissolution, and intramitochondrial vacuolization in GBM cells. Notably, in FOSL2-knockout GBM xenograft models, the Erastin+TMZ treatment group exhibited the lowest expression of Ki-67, GPX4, and SLC7A11. Together, our findings reveal the prominent role of FOSL2 in regulating ferroptosis and highlight the potential therapeutic application of TMZ combined with ferroptosis-inducing drugs.