Inhibiting Ferroptosis through Disrupting the NCOA4–FTH1 Interaction: A New Mechanism of Action
| Autor: | Xiucai Chen, Huihao Zhou, Jun Xu, Qingyun Tan, Qiong Gu, Yuying Fang |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Programmed cell death
010405 organic chemistry Chemistry General Chemical Engineering General Chemistry Oxidative phosphorylation 010402 general chemistry Ligand (biochemistry) 01 natural sciences 0104 chemical sciences Cell biology Mechanism of action Nuclear receptor Coactivator medicine medicine.symptom Receptor QD1-999 Intracellular Research Article |
| Zdroj: | ACS Central Science, Vol 7, Iss 6, Pp 980-989 (2021) ACS Central Science |
| ISSN: | 2374-7951 2374-7943 |
| DOI: | 10.1021/acscentsci.0c01592 |
| Popis: | 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. New ferroptosis inhibitory mechanism is described. A novel ferroptosis inhibitor 9a disrupts the protein−protein interaction of NCOA4 and ferritin to inhibit ferroptosis. |
| Databáze: | OpenAIRE |
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