Ferroptotic stress promotes proneural-to-mesenchymal transition in glioblastoma through the FBXL14–SNAI1 axis

Glioblastoma (GBM) exhibits marked cellular plasticity, and the transition from proneural (PN)-like to mesenchymal (MES)-like states is closely linked to aggressive progression, therapeutic resistance, and poor outcome. Although ferroptosis has been widely studied as an anticancer vulnerability, whether ferroptotic stress actively reshapes glioma cell states remains unclear. Here, we show that ferroptosis defense and oxidative stress adaptation programs are enriched in MES glioma and progressively increase along the PN-to-MES trajectory. MES-like glioma cells maintain a more stable ferroptosis-defense state, whereas PN-like glioma stem cells (GSCs) are more prone to lipid ROS accumulation and redox perturbation under ferroptotic stress. Sustained ferroptotic stress drives PN-like GSCs toward a MES-like state, accompanied by enhanced invasion and increased ferroptosis-defense capacity. Mechanistically, Snail1 acts as a central transcriptional effector of this process by activating MES-associated genes, including CD44 and CHI3L1. Notably, Snail1 accumulation is mediated not by transcriptional induction, but by protein stabilization through suppression of FBXL14-dependent ubiquitin–proteasome degradation. Pharmacological inhibition of the Snail1 axis by CYD19 blocks ferroptotic stress-induced mesenchymal remodeling and enhances temozolomide efficacy in orthotopic glioma models. Together, these findings identify ferroptotic stress as a driver of GBM state plasticity and define the FBXL14–Snail1 axis as a therapeutically targetable mechanism linking redox adaptation to mesenchymal progression.