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Article Dans Une Revue Nature Communications Année : 2022

Non-classical ferroptosis inhibition by a small molecule targeting PHB2

Résumé

Ferroptosis is a new type of programmed cell death characterized by iron-dependent lipid peroxidation. Ferroptosis inhibition is thought as a promising therapeutic strategy for a variety of diseases. Currently, a majority of known ferroptosis inhibitors belong to either antioxidants or iron-chelators. Here we report a new ferroptosis inhibitor, termed YL-939, which is neither an antioxidant nor an iron-chelator. Chemical proteomics revealed the biological target of YL-939 to be prohibitin 2 (PHB2). Mechanistically, YL-939 binding to PHB2 promotes the expression of the iron storage protein ferritin, hence reduces the iron content, thereby decreasing the susceptibility to ferroptosis. We further showed that YL-939 could substantially ameliorate liver damage in a ferroptosis-related acute liver injury model by targeting the PHB2/ferritin/iron axis. Overall, we identified a non-classical ferroptosis inhibitor and revealed a new regulation mechanism of ferroptosis. These findings may present an attractive intervention strategy for ferroptosis-related diseases.
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Dates et versions

hal-03942198 , version 1 (16-01-2023)

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Wei Yang, Bo Mu, Jing You, Chenyu Tian, Huachao Bin, et al.. Non-classical ferroptosis inhibition by a small molecule targeting PHB2. Nature Communications, 2022, 13 (1), ⟨10.1038/s41467-022-35294-2⟩. ⟨hal-03942198⟩

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