2. Academic Validation
  3. Nuclear receptor FXR inhibits ferroptosis to alleviate hepatic ischemia-reperfusion injury by targeting GPX4 in a mouse model

Nuclear receptor FXR inhibits ferroptosis to alleviate hepatic ischemia-reperfusion injury by targeting GPX4 in a mouse model

  • J Mol Histol. 2025 Jul 31;56(4):243. doi: 10.1007/s10735-025-10534-z.
Mi Chen # 1,  Shuang Guo # 1,  Xingqiong Huang 1,  Qigui Mo 1,  Qingjie Chen 1,  Shengnan Zhang 2 3,  Youzhi Zhang 4 5,  Chao Liu 6 7
Affiliations

Affiliations

  • 1 Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, Xianning, 437100, PR China.
  • 2 Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, Xianning, 437100, PR China. zsn0106@hbust.edu.cn.
  • 3 , No. 88 Xianning Avenue, Xian'an District, Xianning, 437100, Hubei Province, PR China. zsn0106@hbust.edu.cn.
  • 4 Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, Xianning, 437100, PR China. yzzhang242@hbust.edu.cn.
  • 5 , No. 88 Xianning Avenue, Xian'an District, Xianning, 437100, Hubei Province, PR China. yzzhang242@hbust.edu.cn.
  • 6 Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, Xianning, 437100, PR China. liu_chao@hbust.edu.cn.
  • 7 , No. 88 Xianning Avenue, Xian'an District, Xianning, 437100, Hubei Province, PR China. liu_chao@hbust.edu.cn.
  • # Contributed equally.
PMID: 40742574 DOI: 10.1007/s10735-025-10534-z
Abstract

Ischemia-reperfusion injury is a common complication in hepatic surgery, which seriously affects the surgical prognosis. Ferroptosis is a novel programmed cell death mode involved in hepatic ischemia-reperfusion injury (HIRI). Recent studies have shown that nuclear receptor FXR can alleviate HIRI, but the mechanism is not fully understood. In this study, we explored the potential regulatory mechanism of FXR in HIRI by using wild-type mice, FXR knockout mice, and AML12 cells. Results show that FXR was negatively correlated with HIRI-induced Ferroptosis, and deletion of FXR promotes Ferroptosis induced by HIRI. Activation of FXR was able to promote GPX4 expression and inhibit Ferroptosis. However, the co-treatment of GPX4 inhibitor and FXR ligand weakened the inhibitory effect of FXR on promoting GPX4 expression and Ferroptosis. Luciferase and EMSA results suggest that FXR regulates GPX4 transcriptional expression by binding to DR5 upstream of the GPX4 initiation codon. Our results suggest that FXR can inhibit HIRI-induced Ferroptosis by targeting the transcriptional expression of GPX4. It contributes to a better understanding of the role of FXR in HIRI. In addition, our findings provide potential therapeutic options for the intervention of ischemia-reperfusion injury in surgery.

Keywords

FXR; Ferroptosis; GPX4; Hepatic ischemia-reperfusion injury (HIRI); Nuclear receptor.

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