The subcellular landscape of ferroptosis: A cellular organelle perspective

Abstract

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation. Its execution depends not only on the amount of lipid peroxides, but also on where oxidizable lipids, redox-active iron, reactive oxygen species, and antioxidant defenses are distributed within cells. This review summarizes current evidence for organelle-resolved regulation of ferroptosis and oxidative stress, with emphasis on the endoplasmic reticulum, peroxisomes, mitochondria, lysosomes, lipid droplets, and phase-separated condensates. We discuss how lipid remodeling, ether lipid synthesis, mitochondrial metabolism and local antioxidant defense, ferritinophagy, lysosomal lipid peroxidation, and lipid droplet-mediated fatty acid buffering influence ferroptosis sensitivity. We also summarize how organelle-specific redox defenses and stress-adaptive signaling pathways may shape therapeutic responses. Together, these studies show that ferroptosis is regulated by coordinated changes in lipid metabolism, iron handling, and antioxidant capacity across distinct subcellular compartments.