Phospholipid remodeling as a key regulator of ferroptosis

Ferroptosis is an iron-dependent form of regulated cell death characterized by the accumulation of lipid peroxides in cellular membranes. Cellular susceptibility to ferroptosis is strongly influenced by membrane phospholipid composition, which is dynamically regulated through phospholipid remodeling. Phospholipid remodeling, also known as the Lands' cycle, drives the replacement of fatty acyl chains in phospholipids through the coordinated actions of phospholipases A, acyl-CoA synthetases (ACSLs), and lysophospholipid acyltransferases (LPLATs). Phospholipid remodeling critically influences ferroptosis sensitivity by regulating the balance between phospholipid species containing polyunsaturated fatty acids (PUFAs), which promote lipid peroxidation, and those containing saturated/monounsaturated fatty acids, which confer resistance. Recent studies have identified key remodeling enzymes, including ACSL4 and LPLAT12, as central drivers of ferroptosis through the generation of PUFA-containing phospholipids, while other enzymes suppress ferroptosis by limiting lipid peroxidation or removing oxidized phospholipids. In parallel, specific phospholipid species-including arachidonic acid- and adrenic acid-containing phospholipids, di-PUFA phospholipids, and other oxidizable lipid classes-have emerged as critical contributors to ferroptosis. Collectively, these findings highlight phospholipid remodeling as a central determinant of ferroptosis by shaping the membrane lipid landscape.