Abstract Temozolomide (TMZ) resistance remains a major obstacle in glioma treatment. Ferroptosis, an iron-dependent, lipid peroxidation–driven regulated cell death, represents a promising alternative strategy. We investigated molecular determinants of ferroptosis sensitivity in TMZ-resistant glioma, focusing on HIF-1α and oxidative stress. One TMZ-sensitive (U251) and three TMZ-resistant (T98, U118, LN18) cell lines were treated with ferroptosis inducers (Erastin, FIN56, RSL3). Viability, ROS (total and mitochondrial), lipid peroxidation, and ferroptosis-related gene/protein expression were assessed. MitoTEMPO and deferoxamine (DFX) were used to probe mitochondrial ROS and iron dependence, respectively. Integrated metabolomic–proteomic analyses and an orthotopic U118-Luc model supported in vitro findings. Ferroptosis inducers reduced viability and bypassed TMZ resistance in vitro and suppressed tumor growth in vivo with partial body-weight loss. Resistant cells displayed high HIF-1α with elevated GSH/NRF2 activity and reduced lipid peroxidation. Treatments increased oxidative stress and downregulated GPX4 , xCT , FSP1 , and ATF4 ; MitoTEMPO rescued cells, implicating mitochondrial ROS. Ferroptosis induction reduced HIF-1α expression/nuclear localization and decreased HIF-1α / VEGF / SOX2 / NRF2 in tumor tissue, supporting therapeutic potential.
Remedia et al. (Fri,) studied this question.