Inhibiting Ferroptosis through Disrupting the NCOA4–FTH1 Interaction: A New Mechanism of Action

Abstract

Ferroptosis is an iron-dependent form of oxidative cell death, and the inhibition of ferroptosis is a promising strategy with which to prevent and treat neurological diseases. Herein we report a new ferroptosis inhibitor <b>9a</b> with a novel mechanism of action. It is demonstrated that nuclear receptor coactivator 4 (NCOA4), a cargo receptor for ferritinophagy, is the target of <b>9a</b>. Compound <b>9a</b> blocks ferroptosis by reducing the amount of bioavailable intracellular ferrous iron through disrupting the NCOA4-FTH1 protein-protein interaction. Further studies indicate that <b>9a</b> directly binds to recombinant protein NCOA4^383-522 and effectively blocks the NCOA4^383-522-FTH1 interaction. In a rat model of ischemic stroke, <b>9a</b> significantly ameliorates the ischemic-refusion injury. With the first ligand <b>9a</b>, this work reveals that NCOA4 is a promising drug target. Additionally, <b>9a</b> is the first NCOA4-FTH1 interaction inhibitor. This work paves a new road to the development of ferroptosis inhibitors against neurological diseases.