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

Nonalcoholic fatty liver disease (NAFLD) is an increasing global health concern. Approximately one quarter of patients have nonalcoholic 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. This study aims to explore the role of iron in macrophages in NASH development. Conditional macrophage-specific H-ferritin knockout (LysM-Cre <i>Fth</i>KO) mice were divided into four groups: wild-type (WT) and LysM-Cre <i>Fth</i>KO mice fed a normal diet, and WT and LysM-Cre <i>Fth</i>KO mice with NASH model induced by diet and chemical. Histological analysis revealed that the NAFLD activity score and hepatic fibrosis were alleviated in the livers of LysM-Cre <i>Fth</i>KO 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 <i>Fth</i>KO 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 <i>Fth</i>KO mice with NASH. In addition, hepatocellular carcinoma development was observed in 90% of WT mice and 62% of LysM-Cre <i>Fth</i>KO mice 30 wk after NASH induction, with tumor number and size being lower in LysM-Cre <i>Fth</i>KO mice. Deletion of macrophage H-ferritin 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.<b>NEW & NOTEWORTHY</b> NASH is a type of NAFLD with severe damage such as inflammation and fibrosis, which causes hepatocellular carcinoma. This study explores macrophage-specific iron involvement in NASH using LysM-Cre <i>Fth</i>KO mice. Results show that knocking out H-ferritin in macrophages reduces NASH-related inflammation, fibrosis, and oxidative stress compared with wild-type mice. Tumor occurrence was lower in LysM-Cre <i>Fth</i>KO mice. These findings suggest that macrophage iron modulation may be a therapeutic target for NASH treatment.