Non-classical ferroptosis inhibition by a small molecule targeting PHB2

Wei Yang, Bo Mu, Jing You, Chenyu Tian, Huachao Bin, Zhiqiang Xu, Liting Zhang, Ronggang Ma, Ming Wu, Guo Zhang, Chong Huang, Linli Li, Zhenhua Shao, Lunzhi Dai, Laurent Désaubry and Shengyong Yang ()
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Wei Yang: Sichuan University
Bo Mu: Sichuan University
Jing You: Sichuan University
Chenyu Tian: Sichuan University
Huachao Bin: Sichuan University
Zhiqiang Xu: Sichuan University
Liting Zhang: Sichuan University
Ronggang Ma: Sichuan University
Ming Wu: Sichuan University
Guo Zhang: Sichuan University
Chong Huang: Sichuan University
Linli Li: Sichuan University
Zhenhua Shao: Sichuan University
Lunzhi Dai: Sichuan University
Laurent Désaubry: INSERM-University of Strasbourg, Center of Research in Biomedicine of Strasbourg (CRBS)
Shengyong Yang: Sichuan University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-35294-2

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