Indole‐3‐Acetic Acid Attenuates Metabolic‐Associated Steatohepatitis via APC to Inhibit β‐Catenin/Wnt Pathway

BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) with the end stage of cirrhosis and hepatocyte carcinoma is becoming the major cause of liver transplantation and liver-related death. Few drugs are effective and approved by FDA for treating advanced MASH and fibrosis. Recent evidence has implicated that gut microbiota and their metabolites are related to MASH. Indole-3-acetic acid (IAA), a tryptophan metabolite derived from the gut microbiota, has emerged as a promising therapeutic candidate for MASH-associated liver fibrosis. This study aimed to explore the role of IAA in MASH-associated liver fibrosis and its potential mechanism. METHODS: CDAHFD-fed and HFHFrC-fed mice models were used to investigate the in vivo effect of IAA on MASH associated fibrosis. Free fatty lipid induced MASH model in human-derived 3D liver spheroids was established to validate the effect in vitro. RNA sequencing was performed to elucidate the underlying molecular mechanism of IAA. RESULTS: The oral administration of IAA significantly alleviated pathological characteristics and improved serum indicators of MASH-associated fibrosis mice. These results were corroborated in a 3D liver spheroids model. Mechanistically, IAA upregulated adenomatous polyposis coli (APC) expression, thereby inhibiting the nucleus translocation of β-catenin. The blockade of the β-catenin/Wnt pathway subsequently suppressed the activation of proliferation of hepatic stellate cells (HSCs). CONCLUSIONS: IAA acts as an antagonist of β-catenin/Wnt pathway via promoting APC expression and inhibiting β-catenin nucleus translocation. Consequently, IAA mitigates MASH-associated liver fibrosis by inhibiting HSCs activation and proliferation.