Inhibiting Ferroptosis through Disrupting the NCOA4–FTH1 Interaction: A New Mechanism of Action,ACS Central Science

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Inhibiting Ferroptosis through Disrupting the NCOA4–FTH1 Interaction: A New Mechanism of Action
ACS Central Science ( IF 12.7 ) Pub Date : 2021-05-06 , DOI: 10.1021/acscentsci.0c01592
Yuying Fang ₁ , Xiucai Chen ₁ , Qingyun Tan ₁ , Huihao Zhou ₁ , Jun Xu ₁ , Qiong Gu ₁

Affiliation

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.

中文翻译：

通过破坏 NCOA4-FTH1 相互作用抑制铁死亡：一种新的作用机制

铁死亡是一种铁依赖形式的氧化性细胞死亡，抑制铁死亡是预防和治疗神经系统疾病的一种很有前景的策略。在此，我们报告了一种具有新作用机制的新型铁死亡抑制剂9a。已证明核受体共激活因子 4 (NCOA4)，一种铁蛋白吞噬的货物受体，是9a的目标。化合物9a通过破坏 NCOA4-FTH1 蛋白质-蛋白质相互作用来减少生物可利用的细胞内亚铁的量，从而阻断铁死亡。进一步研究表明，9a直接结合重组蛋白 NCOA4 ^383-522并有效阻断 NCOA4 ^383-522–FTH1 交互。在缺血性中风的大鼠模型中，9a显着改善了缺血再灌注损伤。有了第一个配体9a，这项工作表明 NCOA4 是一个有前途的药物靶点。此外，9a是第一个 NCOA4-FTH1 相互作用抑制剂。这项工作为开发针对神经系统疾病的铁死亡抑制剂铺平了新的道路。

更新日期：2021-06-23

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