Fig. 1: Metabolic rewiring and ferroptosis resistance in glioblastoma.
From: Harnessing ferroptosis to transform glioblastoma therapy and surmount treatment resistance
This schematic illustrates the key molecular pathways regulating ferroptosis in glioblastoma. The left side represents ferroptosis-promoting mechanisms, including iron uptake via transferrin receptor (TFRC) and ferritinophagy, polyunsaturated fatty acid (PUFA) activation by ACSL4 and LPCAT3. Lipid peroxidation is further facilitated by pro-oxidant enzymes such as POR and ALOX. Concurrently, mitochondrial stress generates superoxide ions, and disruption of the inner mitochondrial membrane releases these reactive species into the cytoplasm, promoting PUFA oxidation. Additionally, NOX5-driven Fenton reactions elevate reactive oxygen species (ROS) levels, contributing to ferroptotic cell death. Depletion of intracellular glutathione (GSH), mediated by reduced cystine import via system Xc− (SLC7A11/xCT), impairs GPX4 function, enabling lethal accumulation of lipid peroxides (LPO). The right-side highlights ferroptosis-inhibitory mechanisms induced by glioblastoma. These include GPX4-mediated detoxification of LPO using GSH, lipid radical scavenging via the CoQ10/FSP1 and DHODH pathways, and antioxidant gene expression regulated by Nrf2. Iron homeostasis is maintained through export (SLC40A1), ferritin-mediated sequestration (FTH1/FTL), and extracellular vesicle (EV)-mediated iron efflux, limiting labile iron pools and suppressing ROS production. Together, these networks determine cellular sensitivity to ferroptosis and highlight potential therapeutic targets in glioblastoma. The figure was created with BioRender.com.
