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 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 NCOA4383–522 and effectively blocks the NCOA4383–522–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.
Highlights
Ferroptosis, a new type of programmed cell death, is characterized by excessive iron-dependent lipid peroxidation.[1,2] In the presence of ferrous iron, the abnormal accumulation of lipid hydroperoxides results in membrane destruction and irreversible cell death.[3]
We found that the cotreatment of HT22 cells with 9a, the classic ferroptosis inhibitor Fer-1, or DFO significantly reduced the level of cell death from cysteine depletion (Figure S2A)
With the assay of Buthionine sulfoximine (BSO)-induced ferroptosis in HT22 cells, we found that 9a dose-dependently prevented cell death (Figure S2B)
Summary
Ferroptosis, a new type of programmed cell death, is characterized by excessive iron-dependent lipid peroxidation.[1,2] In the presence of ferrous iron, the abnormal accumulation of lipid hydroperoxides results in membrane destruction and irreversible cell death.[3]. 9a inhibited the endogenous NCOA4 interaction with FTH1 (Figure 5B) These results demonstrate that 9a is a potent inhibitor of the NCOA4−FTH1 interaction in cells. In vivo data demonstrate that 9a effectively alleviates cerebral ischemic damage through inhibiting ferroptosis
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