Hepcidin inhibits hepatocyte apoptosis through the PERK pathway in acute liver injury and fibrosis.

Abstract

Background: Hepcidin, a peptide hormone primarily produced by the liver, regulates iron metabolism by interacting with its receptor, ferroportin. Studies have demonstrated that hepcidin participates in the progression of liver fibrosis by regulating HSC activation, but its regulatory effect on hepatocytes remains largely unknown.

Methods: A carbon tetrachloride (CCl4)-induced liver fibrosis model was established in C57BL/6 wild-type (WT) and hepcidin knockout (Hamp-/-) mice. Liver injury and inflammation were assessed in WT and Hamp-/- mice at 24 and 48 hours following acute CCl4 exposure. In addition, transcriptomic sequencing of primary hepatocytes was performed to compare gene expression profiles between WT and Hamp-/- mice 24 hours after liver injury. The function of the identified molecule Eif2ak3/PERK (protein kinase R(PKR)-like endoplasmic reticulum kinase), was evaluated both in vitro and in vivo.

Results: We found that serum hepcidin significantly increased during the progression of liver fibrosis induced by CCl4 and bile duct ligation. In addition, CCl4-treated Hamp-/- mice developed more severe liver injury, liver fibrosis, and hepatocyte apoptosis, with elevated Bax and decreased Bcl-2 expression, compared to the WT mice. Transcriptomic analysis of primary hepatocytes revealed that PERK was upregulated in Hamp-/- mice after CCl4 treatment, promoting apoptosis by regulating Bax and Bcl-2 expression. Subsequently, we demonstrated that hepcidin prevents hepatocyte apoptosis by inhibiting PERK both in vitro and in vivo.

Conclusions: Hepcidin inhibits hepatocyte apoptosis through suppression of the PERK pathway, highlighting its protective role in liver fibrosis and identifying a potential therapeutic target for the treatment of liver fibrosis.