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

Autoimmune hepatitis (AIH) is increasingly affecting human health but pharmacotherapies remain to be iden-tified. 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.

Automated summary

This study revealed the protective role of fibroblast growth factor 4 (FGF4) in autoimmune hepatitis (AIH) by inhibiting ferroptosis of hepatocytes. The expression of FGF4 was found to be associated with the severity of ferroptosis in AIH liver injury, and treatment with Ferrostatin-1 (Fer-1) effectively reversed this effect. Additionally, exogenous recombinant FGF4 (rFGF4) was shown to mitigate liver damage and ferroptosis, accompanied by the upregulation of CISD3, Nrf2, and HO-1.