Ferrostatins Inhibit Oxidative Lipid Damage and Cell Death in Diverse Disease Models
Rachid Skouta, Scott J. Dixon, Jianlin Wang, Denise Dunn, Marina Orman, Kenichi Shimada, Paul A. Rosenberg, Donald C. Lo, Joel M. Weinberg, Andreas Linkermann, Brent R. Stockwell
Abstract
Ferrostatin-1 (Fer-1) inhibits ferroptosis, a form of regulated, oxidative, nonapoptotic cell death. We found that Fer-1 inhibited cell death in cellular models of Huntington's disease (HD), periventricular leukomalacia (PVL), and kidney dysfunction; Fer-1 inhibited lipid peroxidation, but not mitochondrial reactive oxygen species formation or lysosomal membrane permeability. We developed a mechanistic model to explain the activity of Fer-1, which guided the development of ferrostatins with improved properties. These studies suggest numerous therapeutic uses for ferrostatins, and that lipid peroxidation mediates diverse disease phenotypes.