Iron and ferroptosis: A still ill-defined liaison

Ferroptosis is a recently described form of regulated necrotic cell death, which appears to contribute to a number of diseases, such as tissue ischemia/reperfusion injury, acute renal failure, and neurodegeneration. A hallmark of ferroptosis is iron-dependent lipid peroxidation, which can be inhibited by the key ferroptosis regulator glutathione peroxidase 4(Gpx4), radical trapping antioxidants and ferroptosis-specific inhibitors, such as ferrostatins and liproxstatins, as well as iron chelation. Although great strides have been made towards a better understanding of the proximate signals of distinctive lipid peroxides in ferroptosis, still little is known about the mechanistic implication of iron in the ferroptotic process. Hence, this review aims at summarizing recent advances in our understanding to what is known about enzymatic and nonenzymatic routes of lipid peroxidation, the involvement of iron in this process and the identification of novel players in ferroptotic cell death. Additionally, we review early works carried out long time before the term "ferroptosis" was actually introduced but which were instrumental in a better understanding of the role of ferroptosis in physiological and pathophysiological contexts. © 2017 IUBMB Life, 69(6):423-434, 2017.