2. Academic Validation
  3. Mifepristone protects acetaminophen induced liver injury through NRF2/GSH/GST mediated ferroptosis suppression

Mifepristone protects acetaminophen induced liver injury through NRF2/GSH/GST mediated ferroptosis suppression

  • Free Radic Biol Med. 2024 Jun 19:222:229-243. doi: 10.1016/j.freeradbiomed.2024.06.014.
Yanyun Shi 1,  Nahua Xu 2,  Baiping Liu 3,  Yanni Ma 4,  Xuemei Fu 3,  Yingying Shang 4,  Qilin Huang 5,  Qi Yao 6,  Jieping Chen 7,  Hui Li 8
Affiliations

Affiliations

  • 1 GuiZhou University Medical College, Guiyang, 550025, China.
  • 2 Department of Hematology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China.
  • 3 Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children (Women and Children's Hospital of Chongqing Medical University), Chongqing, 401120, China.
  • 4 Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • 5 GuiZhou University Medical College, Guiyang, 550025, China; Department of Neurosurgery, Guiqian International General Hospital, Changpo Road, Wudang District, Guiyang, 550000, China. Electronic address: hqlxqyy@sina.com.
  • 6 Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China. Electronic address: yaoqi_wh@163.com.
  • 7 Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China. Electronic address: chenjpxn@163.com.
  • 8 Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children (Women and Children's Hospital of Chongqing Medical University), Chongqing, 401120, China; Department of Hematology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China. Electronic address: lihui_wh1983@163.com.
PMID: 38906233 DOI: 10.1016/j.freeradbiomed.2024.06.014
Abstract

Ferroptosis is a form of iron-dependent cell death that has attracted significant attention for its potential role in numerous diseases. Targeted inhibition of Ferroptosis could be of potential use in treating diseases: such as drug induced liver injury (DILI). Ferroptosis can be antagonized by the xCT/GSH/GPX4, FSP1/CoQ10, DHODH/CoQ10, GCH1/BH4, and NRF2 pathways. Identifying novel anti-ferroptosis pathways will further promote our understanding of the biological nature of Ferroptosis and help discover new drugs targeting Ferroptosis related human diseases. In this study, we identified the clinically used drug mifepristone (RU486) as a novel Ferroptosis inhibitor. Mechanistically, RU486 inhibits Ferroptosis by inducing GSH synthesis pathway, which supplies GSH for glutathione-S-transferase (GST) mediated 4-HNE detoxification. Furthermore, RU486 induced RLIP76 and MRP1 export 4-HNE conjugate contributes to its anti-ferroptosis activity. Interestingly, RU486 induced GSH/GSTs/RLIP76&MRP1 anti-ferroptosis pathway acts independent of classic anti-ferroptosis systems: including xCT/GSH/GPX4, FSP1, DHODH, GCH1, SCD1 and FTH1. Moreover, NRF2 was identified to be important for RU486's anti-ferroptosis activity by inducing downstream gene expression. Importantly, in mouse model, RU486 showed strong protection effect on acetaminophen (APAP)-induced acute liver injury, evidenced by decreased ALT, AST level and histological recovery after APAP treatment. Interestingly, RU486 also decreased oxidative markers, including 4-HNE and MDA, and induced NRF2 activation as well as GSTs, MRP1 expression. Together, these data suggest NRF2/GSH/GST/RLIP76&MRP1 mediated detoxification pathway as an important independent anti-ferroptosis pathway act both in vitro and in vivo.

Keywords

Acute liver injury; Ferroptosis; GSH; GST; NRF2; RU486.

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