Curcumin alleviates metabolic dysfunction-associated steatotic liver disease via gut microbiota-dependent epigenetic alterations

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly prevalent, yet effective therapies remain limited. Curcumin (Cur), a polyphenol with well-documented metabolic benefits, shows therapeutic promise in MASLD, but its efficacy and underlying mechanisms remain incompletely understood. A meta-analysis of seven clinical studies indicated that Cur supplementation reduced serum aminotransferase levels, supporting its potential clinical benefit. In high-fat diet (HFD)-fed rats, Cur reduced hepatic lipid accumulation and metabolic dysfunction, whereas these effects were markedly weakened in antibiotic-induced pseudo-germ-free rats, indicating microbiota dependence. Fecal microbiota transplantation from Cur-treated donors transferred these metabolic and histological benefits to antibiotic-conditioned recipients. Fecal 16S rRNA sequencing identified Clostridium_sensu_stricto_1 (C. sensu) as a Cur-suppressed, pro-steatotic taxon, and targeted reconstitution of this taxon abolished Cur-mediated protection. Untargeted hepatic metabolomics and liquid chromatography-mass spectrometry identified kynurenine (KYN) as a C. sensu-derived metabolite and showed that Cur reduced hepatic KYN accumulation. Integrated H3K27ac ChIP-seq, bulk RNA-seq, and single-cell analyses pinpointed hepatocyte-enriched CEBPB as a key epigenetically regulated effector. Luciferase reporter assays, ChIP-qPCR, and gain- and loss-of-function experiments showed that KYN activated the aryl hydrocarbon receptor (AHR), increased H3K27ac enrichment at the Cebpb locus, and induced Cebpb transcription. CEBPB knockdown blocked KYN-induced PI3K-AKT activation and lipid accumulation, whereas in vivo KYN supplementation largely reversed Cur-mediated protection. Collectively, this study reveals a novel gut-liver axis in MASLD pathogenesis, demonstrating that Cur alleviates hepatic steatosis by targeting the microbiota-KYN-AHR-H3K27ac-Cebpb epigenetic axis, positioning Cur supplementation and KYN modulation as promising therapeutic strategies for MASLD intervention.