Super-enhancer-driven recruitment of C/EBPβ by SULT1B1 is implicated in metabolic dysfunction-associated steatotic liver disease progression

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) disrupts core hepatic physiological functions, with super-enhancers (SEs) playing a pivotal role in orchestrating the expression of genes associated with disease pathogenesis. This study aimed to elucidate the regulatory mechanisms of SEs in MASLD pathogenesis. METHODS: We conducted genome-wide H3K27ac profiling and Rank Ordering of SEs (ROSE) in a high-fat diet (HFD)-induced rat model to characterize histone modification and SE reprograming. Integrative analysis of ChIP-Seq and RNA-Seq, combined with transcription factor (TF) binding analysis and siRNA knockdown, was performed to investigate the regulatory mechanisms of SEs, while single-cell RNA sequencing analysis revealed cell-type-specific expression patterns. In vitro experiments further evaluated JQ1-mediated SE inhibition using human and rat hepatocyte cell lines. RESULTS: We observed significant H3K27ac remodeling and transcriptional reprogramming in both MASLD patients and HFD-induced rat models, highlighting epigenetic dysregulation in MASLD progression. Nineteen differential active SEs were identified in the rat model, with SULT1B1 emerging as a core SE-associated gene. Mechanistic analyses revealed that the TF C/EBPβ promotes SULT1B1 transcription through H3K27ac modification. Single-cell analysis further localized this regulatory axis specifically to hepatocytes. Functionally, targeted inhibition of the SE suppressed SULT1B1 expression and significantly mitigated lipid accumulation in both human and rat hepatocytes, supporting its pathogenic role in MASLD. CONCLUSIONS: Our study establishes a mechanistic link between epigenetic-driven SULT1B1 overexpression and MASLD pathogenesis, highlighting SE mediated H3K27ac/C/EBPβ/SULT1B1 axis emerges as a critical regulatory pathway in MASLD, which may offer new therapeutic targets and strategies for treating metabolic liver diseases.