Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis

TLDR

Ferroptosis is a regulated cell death triggered by loss of GPX4 phospholipid peroxidase activity and lethal ROS accumulation, yet the precise interaction of GPX4 inhibitors and the reactive species driving the process remain unclear. We mapped a ligand‑binding site on GPX4, identified the specific lipids oxidized during ferroptosis, and demonstrated that lipoxygenases and phosphorylase kinase G2 are key drivers of lipid peroxidation, revealing a novel mechanism and suggesting new pharmacological interventions.

Abstract

Significance Ferroptosis is a regulated form of cell death induced by loss of glutathione peroxidase 4 (GPX4) phospholipid peroxidase activity and lethal accumulation of reactive oxygen species. Small-molecule inhibitors of GPX4 induce ferroptosis; however, the interaction between these inhibitors and GPX4 has remained elusive, as has the identity of the reactive oxygen species that drive execution of ferroptosis. We identified here a ligand-binding site on GPX4 and determined the specific lipids oxidized during ferroptosis. We further identified two key drivers of lipid peroxidation during ferroptosis: lipoxygenases and phosphorylase kinase G2. These findings reveal a previously enigmatic mechanism of ferroptotic lipid peroxide generation and suggest new strategies for pharmacological control of ferroptosis and diseases associated with this mode of cell death.