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

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

Automated summary

This study introduces a novel ferroptosis inhibitor, 9a, which blocks ferroptosis by disrupting the NCOA4-FTH1 protein-protein interaction and reducing the amount of bioavailable intracellular ferrous iron. The inhibitor shows promise in ameliorating ischemic-reperfusion injury in a rat model of ischemic stroke, suggesting potential as a drug target for neurological diseases.