Ferroptosis: Oxidative stress and pathophysiology

Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides. It is defined as a form of programmed cell death involving the accumulation of lipid hydroperoxides which can be suppressed by iron chelators and lipophilic antioxidants. Ferroptosis-inducing factors can affect glutathione peroxidase directly or indirectly through different pathways, resulting in a decrease in antioxidant capacity and accumulation of reactive lipid species (RLS) in cells, ultimately leading to oxidative cell death. Recent studies have shown that ferroptosis is closely related in the pathophysiology of many diseases, such as tumors, nervous system diseases, ischemia-reperfusion injury, kidney injury, and blood diseases. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer’s, Huntington’s, and Parkinson’s diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals; it is also implicated in heat stress in plants. It is characterized by the loss of activity of enzyme glutathione peroxidase 4 (GPX4), which results in the accumulation of lethal lipid hydroperoxides. It inhibits GPX4 indirectly through blocking system Xc, which is a glutamate/cystine antiporter that exports intracellular glutamate in exchange for extracellular cystine to generate glutathione.