Lipid Metabolism and Ferroptosis

Ferroptosis is an oxidative, iron‐dependent form of non‐apoptotic cell death that contributes to several forms of pathology and may be exploitable for cancer therapy. Ferroptosis can be induced using small molecule inhibitors of the plasma membrane cystine/glutamate antiporter system x c ‐ or the glutathione‐dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4). The execution of ferroptosis requires membrane lipid peroxidation, but specific lipids and lipid metabolic enzymes that are involved in this process are only partly characterized. How ferroptosis sensitivity relates to other fundamental cellular processes such as the cell cycle is also unclear. We find that inhibition of the Rb‐E2F cell cycle pathway causes downregulation of specific lipid metabolic enzymes, leading to an increase in polyunsaturated phospholipid abundance. In turn, this metabolic alteration specifically enhances ferroptosis sensitivity. Drugs that inhibit Rb‐E2F pathway function synergize with a ferroptosis‐inducing small molecule to arrest tumor growth in vivo. These results suggest that ferroptosis sensitivity may be linked to cell cycle progression through specific alterations in membrane phospholipid composition.