Metabolic regulation of ferroptosis in cancer: mechanisms, pharmacological inducers, and translational challenges.

Resistance to traditional apoptosis remains a central obstacle in oncology, especially in tumors that survive chemotherapy, targeted therapy, or immune pressure by acquiring metabolic plasticity. Ferroptosis, a non-apoptotic form of regulated cell death driven by iron-dependent lipid peroxidation, offers a mechanistically distinct opportunity to eliminate these refractory malignant states. In this review, we organize the field around three metabolic layers that govern ferroptosis in cancer: mobilizable iron pools and Fenton chemistry, lipid remodeling and membrane oxidation, and the dynamic balance between reactive oxygen species generation and antioxidant buffering. Rather than treating ferroptosis as a universal opportunity across all tumors, we emphasize how these layers create context-dependent liabilities in therapy-resistant disease. We then connect these layers to clinically relevant tumor contexts, including drug-tolerant persister cells, hypoxic solid tumors, and antioxidant-addicted cancer populations. Particular emphasis is placed on why lysosomal iron activation, lipid-droplet buffering, GSH/GPX4/FSP1 plasticity, medicinal chemistry, and nanomedicine-enabled delivery now represent major turning points in the field. By integrating mechanistic depth with translational challenges such as biomarker selection, intratumoral drug delivery, tumor-state heterogeneity, and therapeutic-window control, this review provides a cancer-therapy-oriented framework for the precision deployment of ferroptosis rather than a purely descriptive summary of ferroptosis biology.