Ferrostatins Inhibit Oxidative Lipid Damage and Cell Death in Diverse Disease Models

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.

铁抑素-1（Ferrostatin-1, Fer-1）可抑制铁死亡（ferroptosis）——一类受调控的氧化性非凋亡细胞死亡形式。本研究发现，铁抑素-1可在亨廷顿病（Huntington’s disease, HD）、脑室周围白质软化症（periventricular leukomalacia, PVL）及肾功能不全的细胞模型中抑制细胞死亡；铁抑素-1能够抑制脂质过氧化，但无法影响线粒体活性氧生成与溶酶体膜通透性。我们构建了可阐释铁抑素-1作用机制的模型，该模型为开发性能更优的铁死亡抑制剂（ferrostatins）提供了指导。上述研究表明，铁死亡抑制剂具备诸多临床治疗用途，且脂质过氧化介导了多种疾病表型的发生发展。