Iron overload exacerbates metabolic dysfunction-associated steatohepatitis via the microbiota-gut-liver axis through lipopolysaccharide-mediated Akr1b8 activation.

Iron homeostatic is closely linked to the development of metabolic dysfunction-associated steatohepatitis (MASH). However, the underlying mechanisms remain poorly understood. HFE knockout (KO) mice were used to generate mild iron-overload models. MASH was induced by feeding mice a methionine- and choline-deficient (MCD) diet for 4 weeks. Iron overload significantly exacerbated the pathologies of MCD-induced MASH, including liver injury, hepatic lipid accumulation, inflammation, and fibrosis. Additionally, iron overload reshaped the composition of gut microbiota, and fecal microbiota transplantation assay proved that gut microbiota from iron-overload mice contributed to hepatic lipid accumulation in control mice. Furthermore, iron overload-induced dysbacteriosis altered the metabolite profiles, reducing short-chain fatty acid levels and increasing lipopolysaccharide (LPS) levels. Notably, elevated LPS levels upregulated the expression of aldo-keto reductase family 1 member B8 (Akr1b8), which accelerated lipid accumulation and inflammation in hepatocytes. Above results indicated that iron overload promoted MASH progression through the microbiota-gut-liver axis, mediated by LPS-induced activation of Akr1b8. These findings highlight the critical role of iron homeostasis and gut microbiota in MASH pathogenesis.