Oxidative and Antioxidant Systems in Ferroptosis of Cancer: Mechanisms, Regulations, and Therapeutic Targeting

ABSTRACT Ferroptosis is a redox‐governed, non‐apoptotic cell death program driven by iron‐dependent lipid peroxidation. Its execution depends on the balance between reactive oxygen species (ROS) generation and hierarchical antioxidant defenses. Despite extensive biochemical mapping, an integrated framework delineating how diverse redox defense systems converge to dictate ferroptotic sensitivity across tumor contexts remains lacking. This review delineates the hallmarks and molecular mechanisms of ferroptosis, examining how ROS sources within mitochondrial, the endoplasmic reticulum, membranes, and the cytoplasm drive lipid peroxidation. The antioxidant landscape is systematically classified into three functional tiers: (1) the primary canonical glutathione‐GPX4 axis, (2) secondary non‐canonical and radical‐trapping systems including FSP1‐CoQ10, GCH1‐BH4, peroxiredoxins, and vitamin K, and (3) tertiary metabolic support and detoxification systems encompassing thioredoxin, AKR1C enzymes, SOD‐catalase, and NADPH regeneration. The regulation of these defenses by master signaling hubs including NRF2, AMPK‐mTOR, ATF4, STAT3, Wnt/beta‐catenin, p53, and ncRNAs is evaluated, alongside oncogenic metabolic adaptations creating exploitable vulnerabilities in high‐plasticity states including epithelial to mesenchymal transition, cancer stem cells, hypoxic, matrix‐detached, and chemoresistant cells. Tumor microenvironment crosstalk among cancer‐associated fibroblasts and immune effectors, including CD8 + T cells, natural killer cells, macrophages, and myeloid‐derived suppressor cells, and therapeutic strategies spanning pharmacological and nanomaterial‐based approaches are further examined. Collectively, this synthesis furnishes a mechanistic framework for precision exploitation of ferroptosis across oncological contexts.