Ferroptosis, free radicals, and cancer

Abstract Oxidative stress induced by an imbalance between oxidant and antioxidant factors is linked to various types of regulated cell death, which affects many aspects of tumor biology. Ferroptosis is a form of reactive oxygen species-dependent cell death, which is characterized by iron accumulation and lipid peroxidation. Although the direct molecular effector for ferroptosis is not known, ACSL4- and lipoxygenase-mediated production of lipid peroxides play a major role in the induction of ferroptosis. Autophagy, including ferritinophagy, lipophagy, clockophagy, and chaperone-mediated autophagy, contributes to ferroptotic cancer cell death through the upregulation of oxidative injury. In contrast, there are many antioxidant systems or proteins, such as the cystine/glutamate antiporter system xc−, GPX4, and NFE2L2, in place to limit reactive oxygen species-induced ferroptotic cancer cell death. Understanding the types of ferroptosis and their molecular machinery could open new approaches to cancer therapy.