2. Academic Validation
  3. FGF4 improves hepatocytes ferroptosis in autoimmune hepatitis mice via activation of CISD3

FGF4 improves hepatocytes ferroptosis in autoimmune hepatitis mice via activation of CISD3

  • Int Immunopharmacol. 2023 Jan 24;116:109762. doi: 10.1016/j.intimp.2023.109762.
Huimian Jiang 1,  Yan Fang 1,  Yuxin Wang 1,  Ting Li 1,  Hongwei Lin 1,  Jing Lin 1,  Tongtong Pan 1,  Qingxiu Liu 2,  Jiaojian Lv 2,  Dazhi Chen 3,  Yongping Chen 4
Affiliations

Affiliations

  • 1 Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, Wenzhou 325035, China.
  • 2 Department of Infectious Diseases, the People's Hospital of Lishui, Lishui 323000, China.
  • 3 Department of Clinical Medicine, Hangzhou Medical College, Hangzhou 310053, China. Electronic address: [email protected].
  • 4 Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, Wenzhou 325035, China. Electronic address: [email protected].
PMID: 36702076 DOI: 10.1016/j.intimp.2023.109762
Abstract

Autoimmune hepatitis (AIH) is increasingly affecting human health but pharmacotherapies remain to be identified. Growing evidence reveals that Ferroptosis, a newly recognized form of programmed cell death, is critical for AIH. However, the exact mechanisms of the ferroptotic cascade remain elusive. Data in this study showed that Ferroptosis aggravation was associated with protectively-elevated Fibroblast Growth Factor 4 (FGF4) expression in Concanavalin A (ConA)-induced AIH liver injury, with these effects being effectively reversed by Ferrostatin-1 (Fer-1). Moreover, hepatic Fgf4 depletion was more susceptible to lipid peroxidation and iron accumulation, as well as hepatic lesion and inflammation caused by ConA administration. Conversely, treatment with non-mitogenic recombinant FGF4 (rFGF4) mitigated liver damage and hepatocellular Ferroptosis while being accompanied by the upregulation of CDGSH iron-sulfur domain-containing protein 3 (CISD3) in vivo and in vitro. Furthermore, CISD3 overexpression exhibited stronger resistance to Ferroptosis while CISD3 knockdown reduced ferroptotic biomarkers cystine/glutamate transporter (xCT) and Glutathione Peroxidase 4（GPX4) in rFGF4-treated Erastin-induced AML12 cells. In addition, rFGF4 significantly enhanced the levels of heme oxygenase 1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) in ConA-induced AIH mice. Overall, this study showed that FGF4 can act as a phylactic role in AIH progression, with rFGF4 treatment inhibiting Ferroptosis of hepatocytes by increasing CISD3 levels and activating Nrf2/HO-1 signaling.

Keywords

Autoimmune hepatitis; CDGSH iron-sulfur domain-containing protein 3; Ferroptosis; Fibroblast growth factor 4; Heme oxygenase 1; Nuclear factor erythroid 2-related factor 2.

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