Metabolic reprogramming and ferroptosis in cancer: from redox homeostasis to therapeutic vulnerabilities

Cancer cells undergo profound metabolic reprogramming to sustain proliferation and resist cell death, creating exploitable vulnerabilities at the intersection of metabolism, redox homeostasis, and regulated cell death. This review synthesizes recent advances in understanding how dysregulated glucose, lipid, amino acid, and iron metabolism converges on ferroptosis, an iron-dependent cell death driven by lipid peroxidation. We examine the core machinery governing ferroptosis, including iron handling, phospholipid remodeling, and the glutathione-GPX4, FSP1, and DHODH defense systems. The review details how oncogenic drivers and tumor suppressors, notably NRF2, p53, and KRAS, rewire these pathways to modulate ferroptosis sensitivity. We further explore how the tumor microenvironment, through nutrient competition, stromal lipid provision, and immune cell crosstalk, shapes ferroptotic susceptibility and antitumor immunity. Key findings highlight the dual roles of NRF2 in antioxidant defense and immune evasion, the context-dependent contribution of mitochondrial metabolism to lipid peroxide generation, and the therapeutic potential of targeting SCD1, ACSL4, and system xc−. Emerging strategies combining ferroptosis inducers with immunotherapy or targeted agents show preclinical promise, yet significant challenges remain, including metabolic plasticity driving resistance, a lack of validated in vivo biomarkers for lipid peroxidation, and the need for physiologically relevant models to guide clinical translation of ferroptosis-based therapies.