Deletion of H-ferritin in macrophages mitigates the development of steatohepatitis and hepatocellular carcinoma in mice.

Abstract

Background: Nonalcoholic fatty liver disease (NAFLD) is an increasing global health concern. Approximately one-quarter of patients have non-alcoholic steatohepatitis (NASH), which leads to the development of hepatocellular carcinoma. Several studies have shown the involvement of iron in NASH, but it remains unclear which cell of iron is at issue.

Aim: To explore the role of iron in macrophages in NASH development.

Methods: Conditional macrophage-specific H-ferritin knockout (LysM-Cre FthKO) mice were divided into four groups: wild-type (WT) and LysM-Cre FthKO mice fed a normal diet, and WT and LysM-Cre FthKO mice with NASH model induced by diet and chemical.

Results: Histological analysis revealed that the NAS score and hepatic fibrosis were alleviated in the livers of LysM-Cre FthKO mice with NASH compared with WT mice with NASH. The expression and signaling of inflammatory cytokines and fibrosis-related genes were increased in the livers of WT mice with NASH, but not elevated in the livers of LysM-Cre FthKO mice with NASH. Similarly, macrophage infiltration and oxidative stress were augmented in the livers of WT mice with NASH but were inhibited in the livers of LysM-Cre FthKO mice with NASH. Additionally, hepatocellular carcinoma development was observed in 90% of WT mice and 62% of LysM-Cre FthKO mice 30 weeks after NASH induction, with tumor number and size being lower in LysM-Cre FthKO mice.

Conclusions: Deletion of macrophage FTH alleviated NASH development by reducing inflammation, fibrosis, and oxidative stress. The findings of this study highlight macrophage iron levels as a potential therapeutic target in NASH.