2. Academic Validation
  3. Gp78 deficiency in hepatocytes alleviates hepatic ischemia-reperfusion injury via suppressing ACSL4-mediated ferroptosis

Gp78 deficiency in hepatocytes alleviates hepatic ischemia-reperfusion injury via suppressing ACSL4-mediated ferroptosis

  • Cell Death Dis. 2023 Dec 8;14(12):810. doi: 10.1038/s41419-023-06294-x.
Changbiao Li # 1 2 3,  Yichao Wu # 1 2 3,  Kangchen Chen # 3,  Ronggao Chen 4,  Shengjun Xu 1 3,  Beng Yang 4,  Zhengxing Lian 3,  Xiaodong Wang 5,  Kai Wang 1 3,  Haiyang Xie 2 4,  Shusen Zheng 2 6,  Zhikun Liu 7 8,  Di Wang 9 10,  Xiao Xu 11 12 13
Affiliations

Affiliations

  • 1 Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 2 NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China.
  • 3 Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China.
  • 4 Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310003, China.
  • 5 The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
  • 6 Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, 311112, China.
  • 7 Zhejiang University School of Medicine, Hangzhou, 310058, China. [email protected].
  • 8 Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China. [email protected].
  • 9 Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China. [email protected].
  • 10 Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, China. [email protected].
  • 11 Zhejiang University School of Medicine, Hangzhou, 310058, China. [email protected].
  • 12 NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China. [email protected].
  • 13 Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China. [email protected].
  • # Contributed equally.
PMID: 38065978 DOI: 10.1038/s41419-023-06294-x
Abstract

Ferroptosis, which is driven by iron-dependent lipid peroxidation, plays an essential role in liver ischemia-reperfusion injury (IRI) during liver transplantation (LT). Gp78, an E3 ligase, has been implicated in lipid metabolism and inflammation. However, its role in liver IRI and Ferroptosis remains unknown. Here, hepatocyte-specific gp78 knockout (HKO) or overexpressed (OE) mice were generated to examine the effect of gp78 on liver IRI, and a multi-omics approach (transcriptomics, proteomics, and metabolomics) was performed to explore the potential mechanism. Gp78 expression decreased after reperfusion in LT patients and mice with IRI, and gp78 expression was positively correlated with liver damage. Gp78 absence from hepatocytes alleviated liver damage in mice with IRI, ameliorating inflammation. However, mice with hepatic gp78 overexpression showed the opposite phenotype. Mechanistically, gp78 overexpression disturbed lipid homeostasis, remodeling polyunsaturated fatty acid (PUFA) metabolism, causing oxidized lipids accumulation and Ferroptosis, partly by promoting ACSL4 expression. Chemical inhibition of Ferroptosis or ACSL4 abrogated the effects of gp78 on Ferroptosis and liver IRI. Our findings reveal a role of gp78 in liver IRI pathogenesis and uncover a mechanism by which gp78 promotes hepatocyte Ferroptosis by ACSL4, suggesting the gp78-ACSL4 axis as a feasible target for the treatment of IRI-associated liver damage.

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