Ferroptotic mechanisms and therapeutic targeting of iron metabolism and lipid peroxidation in the kidney

Ferroptosis is a mechanism of regulated necrotic cell death characterized by iron-dependent, lipid peroxidation-driven membrane destruction that can be inhibited by glutathione peroxidase 4. Morphologically, it is characterized by cellular, organelle and cytoplasmic swelling and the loss of plasma membrane integrity, with the release of intracellular components. Ferroptosis is triggered in cells with dysregulated iron and thiol redox metabolism, whereby the initial robust but selective accumulation of hydroperoxy polyunsaturated fatty acid-containing phospholipids is further propagated through enzymatic and non-enzymatic secondary mechanisms, leading to formation of oxidatively truncated electrophilic species and their adducts with proteins. Thus, ferroptosis is dependent on the convergence of iron, thiol and lipid metabolic pathways. The kidney is particularly susceptible to redox imbalance. A growing body of evidence has linked ferroptosis to acute kidney injury in the context of diverse stimuli, such as ischaemia–reperfusion, sepsis or toxins, and to chronic kidney disease, suggesting that ferroptosis may represent a novel therapeutic target for kidney disease. However, further work is needed to address gaps in our understanding of the triggers, execution and spreading mechanisms of ferroptosis. Ferroptosis is an iron-dependent mechanism of regulated necrosis that is driven by the robust oxidation of polyunsaturated fatty acid-containing phospholipids. This Review describes the fundamental mechanisms of ferroptosis, the potential contribution of ferroptosis to kidney disease and therapeutic strategies for targeting ferroptosis. Key points Multiple cell death pathways contribute to the pathogenesis of acute and chronic kidney injury; ferroptosis is one such mechanism of regulated necrotic cell death, characterized by marked oxidation of phospholipids containing polyunsaturated fatty acids. Ferroptotic death programs are triggered in cells with dysregulated iron and thiol redox metabolism, leading to robust but selective lipid peroxidation, which is propagated through enzymatic and non-enzymatic mechanisms. The excessive accumulation of hydroperoxy-derivatives of arachidonoyl- and adrenoyl-phosphatidylethanolamines is catalysed by a complex of 15-lipoxygenase with phosphatidylethanolamine-binding protein 1 and represents a potential therapeutic target. GPX4 detoxifies phospholipid hydroperoxides to non-toxic phospholipid alcohols using glutathione as a so