Iron: Regulation, redox homeostasis, and ferroptosis in cancer

Iron is essential for cellular metabolism, redox balance, and proliferation, yet its redox activity generates reactive oxygen species (ROS) that can damage DNA, proteins, and lipids. Cancer cells exploit iron homeostasis mechanisms, including iron regulatory proteins, ferritinophagy, and hypoxia-inducible factors to maintain high intracellular iron, supporting metabolic reprogramming, antioxidant defenses, and therapy resistance. Iron-dependent lipid peroxidation drives ferroptosis, a regulated form of cell death uniquely dependent on iron. Ferroptosis is tightly controlled by metabolic and antioxidant pathways and mitochondrial ROS, as well as by lipid composition and polyunsaturated fatty acid availability. Ferroptosis also intersects with apoptosis and necroptosis, highlighting the central role of iron in cell fate and survival. Dysregulation of these pathways in cancer can sensitize cells to ferroptosis, creating a therapeutic vulnerability. Exploiting ferroptosis through modulation of iron availability, redox defenses, or lipid metabolism offers a promising anticancer strategy. However, tissue-specific iron dynamics, tumor heterogeneity, and interactions within the tumor microenvironment complicate clinical translation. Integrative approaches combining metabolic profiling, genetic analysis, and ferroptosis-targeted interventions will be critical to harness iron-dependent cell death while minimizing systemic toxicity. In this review, we explore the mechanisms through which cancer cells sustain high iron, evading associated toxicities and possible implications for integrating ferroptosis based therapies in clinical oncology.