2. Academic Validation
  3. Oleanolic acid alleviating ischemia-reperfusion injury in rat severe steatotic liver via KEAP1/NRF2/ARE

Oleanolic acid alleviating ischemia-reperfusion injury in rat severe steatotic liver via KEAP1/NRF2/ARE

  • Int Immunopharmacol. 2024 Sep 10:138:112617. doi: 10.1016/j.intimp.2024.112617.
Yilin Pi 1,  Huaiwen Zuo 2,  Yuxin Wang 3,  Weiping Zheng 4,  Huiyuan Zhou 5,  Lamei Deng 6,  Hongli Song 7
Affiliations

Affiliations

  • 1 Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin 300070, PR China. Electronic address: piyilin116@tmu.edu.cn.
  • 2 Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin 300070, PR China. Electronic address: huaiwenzuo@tmu.edu.cn.
  • 3 School of Medicine, Nankai University, Tianjin 300071, PR China. Electronic address: wangyuxin@tmu.edu.cn.
  • 4 Department of Liver Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, PR China; NHC Key Laboratory of Critical Care Medicine, Tianjin 300192, PR China. Electronic address: anzwp@tmu.edu.cn.
  • 5 Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin 300070, PR China. Electronic address: zhouhuiyuan@tmu.edu.cn.
  • 6 Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin 300070, PR China. Electronic address: dlm23@tmu.edu.cn.
  • 7 Department of Liver Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, PR China; Tianjin Key Laboratory of Organ Transplantation, Tianjin 300192, PR China. Electronic address: songhl@tmu.edu.cn.
PMID: 38972213 DOI: 10.1016/j.intimp.2024.112617
Abstract

Severe steatosis in donor livers is contraindicated for transplantation due to the high risk of ischemia-reperfusion injury (IRI). Although Ho-1 gene-modified bone marrow mesenchymal stem cells (HO-1/BMMSCs) can mitigate IRI, the role of gut microbiota and metabolites in this protection remains unclear. This study aimed to explore how gut microbiota and metabolites contribute to HO-1/BMMSCs-mediated protection against IRI in severe steatotic livers. Using rat models and cellular models (IAR20 and THLE-2 cells) of steatotic liver IRI, this study revealed that ischemia-reperfusion led to significant liver and intestinal damage, heightened immune responses, impaired liver function, and altered gut microbiota and metabolite profiles in rats with severe steatosis, which were partially reversed by HO-1/BMMSCs transplantation. Integrated microbiome and metabolome analyses identified gut microbial metabolite oleanolic acid as a potential protective agent against IRI. Experimental validation showed that oleanolic acid administration alone alleviated IRI and inhibited Ferroptosis in both rat and cellular models. Network pharmacology and molecular docking implicated KEAP1/NRF2 pathway as a potential target of oleanolic acid. Indeed, OA experimentally upregulated NRF2 activity, which underlies its inhibition of Ferroptosis and protection against IRI. The gut microbial metabolite OA protects against IRI in severe steatotic liver by promoting NRF2 expression and activity, thereby inhibiting Ferroptosis.

Keywords

Ferroptosis; Gut microbial metabolites; Ischemia–reperfusion injury; Oleanolic acid; Steatotic liver.

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