Non-classical ferroptosis inhibition by a small molecule targeting PHB2

  • Nat Commun. 2022 Dec 3;13(1):7473. doi: 10.1038/s41467-022-35294-2.
Wei Yang  #  1 ,  Bo Mu  #  1  2 ,  Jing You  #  1 ,  Chenyu Tian  #  1 ,  Huachao Bin  #  1 ,  Zhiqiang Xu  1 ,  Liting Zhang  1 ,  Ronggang Ma  1 ,  Ming Wu  1 ,  Guo Zhang  1 ,  Chong Huang  1 ,  Linli Li  3 ,  Zhenhua Shao  1 ,  Lunzhi Dai  1 ,  Laurent Désaubry  4 ,  Shengyong Yang  5
Affiliations
  • 1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 2. North Sichuan Medical College, Nanchong, Sichuan, 637000, China.
  • 3. Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 4. Regenerative Nanomedicine Laboratory (UMR1260), INSERM-University of Strasbourg, Center of Research in Biomedicine of Strasbourg (CRBS), Strasbourg, France.
  • 5. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China. [email protected].
  • # Contributed equally.
PMID: 36463308 DOI: 10.1038/s41467-022-35294-2
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.

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