2. Academic Validation
  3. Inhibition of ferroptosis protects intrahepatic bile duct cells against ischemia-reperfusion and bile salt toxicity

Inhibition of ferroptosis protects intrahepatic bile duct cells against ischemia-reperfusion and bile salt toxicity

  • Biochem Pharmacol. 2025 Mar:233:116788. doi: 10.1016/j.bcp.2025.116788.
Huisheng Zhou 1,  Xi Zhou 1,  Guobin Huang 1,  Yuanyuan Zhao 1,  Peixiang Lan 2,  Zhishui Chen 3
Affiliations

Affiliations

  • 1 Institute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Key Laboratory of Organ Transplantation Ministry of Education NHC Key Laboratory of Organ Transplantation Chinese Academy of Medical Sciences Wuhan China; Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases China.
  • 2 Institute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Key Laboratory of Organ Transplantation Ministry of Education NHC Key Laboratory of Organ Transplantation Chinese Academy of Medical Sciences Wuhan China; Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases China. Electronic address: pxlan@tjh.tjmu.edu.cn.
  • 3 Institute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Key Laboratory of Organ Transplantation Ministry of Education NHC Key Laboratory of Organ Transplantation Chinese Academy of Medical Sciences Wuhan China; Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases China. Electronic address: zschen@tjh.tjmu.edu.cn.
PMID: 39890033 DOI: 10.1016/j.bcp.2025.116788
Abstract

Ischemia-reperfusion injury (IRI) and bile salt toxicity are significant contributors to post-transplant cholangiopathy. Ferroptosis appears to play a critical role in intrahepatic bile duct injury induced by ischemia-reperfusion (I/R) and bile salt toxicity. Our study aimed to elucidate the role of Ferroptosis in bile duct injuries and its potential as a therapeutic target for liver diseases. Mouse models of liver ischemia-reperfusion (I/R) and α-naphthyl isocyanate (ANIT)-induced liver cholestasis were employed to investigate the role of Ferroptosis in intrahepatic bile duct injury in vivo. Hypoxia-reoxygenation (H/R) and bile salt treatment models were utilized to simulate the post-transplant bile duct injury process in vitro. In mouse models of liver I/R and cholestasis, we observed a downregulation of Glutathione Peroxidase 4 (GPX4) and an upregulation of lipid peroxidation levels in bile duct cells. Furthermore, the Ferroptosis inhibitor Liproxstatin-1 (Lip-1) significantly attenuated intrahepatic bile duct injuries. Ferroptosis inhibitors alleviated cell death and lipid peroxide accumulation in human intrahepatic biliary epithelial cells (HiBECs) subjected to H/R or glycochenodeoxycholate (GCDCA) treatment. GCDCA treatment led to Ferroptosis in HiBECs along with ferritin degradation. Inhibition of Autophagy alleviated GCDCA-induced bile duct cell death. Our study suggested that Ferroptosis played an important role of in the intrahepatic bile duct injury during I/R or cholestasis.

Keywords

Autophagy; Bile salt; Biliary epithelial cell; Ferroptosis; Ischemia-reperfusion.

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