Generation of singlet oxygen via iron-dependent lipid peroxidation and its role in Ferroptosis

Ferroptosis is a cell death pathway mediated by iron-dependent accumulation of lipid peroxide. However, the specific downstream molecular events of iron-dependent lipid peroxidation are yet to be elucidated. In this study, based on various spectral analyses, we have found evidence that singlet oxygen is produced through the Russell mechanism during the self-reaction of lipid peroxyl radicals generated via iron-dependent lipid peroxidation regardless of the presence of cholesterol. Significantly reduced generation of singlet oxygen was observed in the absence of iron. The generated singlet oxygen accelerated the oxidative damage of lipid membranes by propagating lipid peroxidation and facilitated ferroptotic cancer cell death initiated by erastin. In this work, singlet oxygen has been revealed to be a new reactive species that participates in ferroptosis, thus improving the understanding on iron-dependent lipid peroxidation and the mechanism of ferroptosis.