Arid1a deficiency promotes metabolic dysfunction-associated steatohepatitis and hepatocellular carcinoma by disrupting the FXR-gut microbiota-bile acid axis

ARID1A is frequently mutated in non-tumorous human tissues and various cancers. However, its role in metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC) onset and progression remains controversial. Given the critical role of the gut-liver axis in MASH and HCC, we hypothesized that the gut microbiota might contribute to ARID1A deficiency-induced liver diseases. Here, we demonstrate that liver-specific Arid1a deficiency drives MASH/HCC development through dysregulated bile acid metabolism and gut microbiota restructuring. Gut microbiota depletion using an antibiotic cocktail attenuates MASH progression and reduces HCC incidence in liver-specific Arid1a -deficient mice. While lipopolysaccharide (LPS) accumulation due to gut barrier dysfunction promotes HCC progression, it does not significantly affect MASH activity or tumor initiation in Arid1a -deficient mice. Mechanistically, ARID1A deficiency reduces chromatin accessibility and impairs SWI/SNF complex binding at the promoter of nuclear receptor FXR, which governs bile acid homeostasis, suppressing FXR transcription. Further analyses in Arid1a -deficient mice reveal altered gut microbiota composition enriched in bile salt hydrolase (BSH) genes and bile acid profiles showing elevated levels of the secondary bile acid taurodeoxycholic acid (TDCA). When administered to mice, TDCA exacerbates liver inflammation and fibrosis specifically in Arid1a -deficient mice by promoting neutrophil infiltration and hepatic stellate cell activation. Therapeutic interventions including vancomycin to eliminate bile acid-metabolizing bacteria, obeticholic acid to activate Fxr, and cholestyramine to excrete bile acids substantially ameliorate MASH pathology in Arid1a -deficient mice. Collectively, our findings establish the ARID1A-FXR-bile acid-gut microbiota axis as a pathogenic driver of MASH and HCC, offering mechanism-based therapeutic strategies for patients with ARID1A mutations. • Arid1a deficiency alters gut microbiota and bile acid homeostasis. • Arid1a deficiency represses Fxr expression. • TDCA aggravates liver inflammation and fibrosis in Arid1a- deficient mice. • Targeting the Fxr-microbiota-bile acid axis alleviates Arid1a deficient MASH.