Lipid Metabolism and Ferroptosis

SIMPLE SUMMARY: Ferroptosis is a type of cell death, which is morphologically and mechanistically distinct from other type of cell death pathways such as apoptosis and necroptosis. Lipid peroxidation is a hallmark of ferroptosis and directly destroys cellular membranes, thereby causing ferroptosis. Since lipid peroxidation, which induces ferroptosis, occurs in polyunsaturated fatty acid on specific phospholipids, various lipid metabolic pathways are involved in lipid peroxidation and ferroptosis. Besides, various metabolic and signaling pathways directly and indirectly regulate lipid peroxidation and ferroptosis. Since ferroptosis is associated with a variety of human diseases such as cancer, myocardial infarction, atherosclerosis, kidney diseases, liver diseases, and neuronal diseases, a better understanding of the regulatory mechanisms of ferroptosis can provide insights and treatment strategies for related diseases. ABSTRACT: Ferroptosis is a type of iron-dependent regulated necrosis induced by lipid peroxidation that occurs in cellular membranes. Among the various lipids, polyunsaturated fatty acids (PUFAs) associated with several phospholipids, such as phosphatidylethanolamine (PE) and phosphatidylcholine (PC), are responsible for ferroptosis-inducing lipid peroxidation. Since the de novo synthesis of PUFAs is strongly restricted in mammals, cells take up essential fatty acids from the blood and lymph to produce a variety of PUFAs via PUFA biosynthesis pathways. Free PUFAs can be incorporated into the cellular membrane by several enzymes, such as ACLS4 and LPCAT3, and undergo lipid peroxidation through enzymatic and non-enzymatic mechanisms. These pathways are tightly regulated by various metabolic and signaling pathways. In this review, we summarize our current knowledge of how various lipid metabolic pathways are associated with lipid peroxidation and ferroptosis. Our review will provide insight into treatment strategies for ferroptosis-related diseases.