Using a combination of genetically engineered mouse glioma models, transcriptomic, functional, and metabolomic studies, in vitro studies using patient-derived cell lines and ex vivo studies with acute slice cultures generated from patient-derived GBM samples, we show that Notch activation at tumor inception can induce a quiescent astrocyte-like persister glioma phenotype with a metabolic profile characterized by alterations in mitochondrial function leading to ROS generation and induction of lipid peroxidation with increased sensitivity to GPX4-driven ferroptosis. The gene discussed is GPX4; the disease is neoplasm.