Ferroptosis: Biological Rust of Lipid Membranes

Iron is an essential element required for growth and proper functioning of the body. However, an excess of labile ferrous iron increases the risk of oxidative stress-induced injury due to the high reactivity of the unpaired reactive electrons of both ferrous iron and oxygen. This high reactivity can be exemplified in the outside world by one of its consequences, rust formation. In cells, this redox-active iron is involved in the formation of lipid radicals. Defect or insufficient membrane-protective mechanisms can result in iron-catalyzed excessive lipid peroxidation and subsequent cell death, now conceptualized as ferroptosis. Growing reports propose the detrimental role of iron and ferroptosis in many experimental disease models such as ischemia-reperfusion, acute and chronic organ injuries. This review first provides a snapshot of iron metabolism, followed by a brief introduction of the molecular mechanisms of ferroptosis, as an iron-dependent lipid peroxidation-driven mode of cell death. Upon describing how iron dysbiosis affects ferroptosis induction, we elaborate on the detrimental role of the iron-ferroptosis axis in several diseases. Despite compelling findings suggesting a role of ferroptosis in experimental animal models, the exact contribution of ferroptosis in human contexts still needs further investigation. Development of reliable ferroptosis biomarkers will be an important step in characterizing ferroptosis in human disease. This can provide therapeutic opportunities aiming at targeting ferroptosis in human diseases. Antioxid. Redox Signal. 35, 487-509.