Ferrostatin-1 (Fer-1) is a potent inhibitor of ferroptosis, a form of regulated, oxidative, nonapoptotic cell death. The study found that Fer-1 inhibited cell death in models of Huntington's disease (HD), periventricular leukomalacia (PVL), and kidney dysfunction. Fer-1 prevented lipid peroxidation but not mitochondrial reactive oxygen species formation or lysosomal membrane permeability. The mechanism of action of Fer-1 was explored, and a mechanistic model was developed to guide the design of improved ferrostatins. These findings suggest that lipid peroxidation mediates diverse disease phenotypes and that ferrostatins have therapeutic potential in various conditions involving oxidative lipid damage and cell death.Ferrostatin-1 (Fer-1) is a potent inhibitor of ferroptosis, a form of regulated, oxidative, nonapoptotic cell death. The study found that Fer-1 inhibited cell death in models of Huntington's disease (HD), periventricular leukomalacia (PVL), and kidney dysfunction. Fer-1 prevented lipid peroxidation but not mitochondrial reactive oxygen species formation or lysosomal membrane permeability. The mechanism of action of Fer-1 was explored, and a mechanistic model was developed to guide the design of improved ferrostatins. These findings suggest that lipid peroxidation mediates diverse disease phenotypes and that ferrostatins have therapeutic potential in various conditions involving oxidative lipid damage and cell death.