Inhibition of Acetylation Activity of p300/ CBP Ameliorates Hepatic Steatosis Through Downregulation of ACSL4

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disorder, with few optimal pharmacotherapies. Ongoing studies are providing evidence that histone acetylation contributes to the progression of MASLD. This study investigated the alterations of specific histone acetylation sites in MASLD tissues and the effects of B029-2, a small-molecule inhibitor targeting p300/CBP acetylation activity, in mouse models of progressive fatty liver disease. METHODS: The acetylation of H3K27/H3K18/H3K9 was assessed in liver samples from MASLD patients and mice. The effect of the B029-2 in MASLD was assessed in MASLD models. A ChIP assay was conducted to investigate the epigenetic regulatory mechanism of ACSL4. Hepatic-specific Acsl4-knockout and overexpression mice were generated to validate the role of ACSL4 in MASLD. RESULTS: We observed a significant increase in p300 HAT activity, p300/CBP-induced H3K18ac and H3K27ac levels in MASLD and B029-2 markedly reduced hepatic steatosis in vitro and in vivo. Transcriptome analysis revealed that B029-2 inhibited the expression of genes in the triglyceride biosynthetic process and long-chain fatty-acyl-CoA biosynthetic process. ChIP assay showed that H3K18ac, H3K27ac and p300 bind to the promoter region of ACSL4, and their binding is reduced by B029-2 treatment. AAV-mediated hepatic-specific overexpression of Acsl4 attenuated the effect of B029-2 on MASLD in mice, while hepatic-specific Acsl4-deficient in mice blocked the effect of B029-2. CONCLUSIONS: p300/CBP-mediated H3K18ac and H3K27ac regulate ACSL4-dependent lipid biosynthesis in MASLD and might be a potential therapeutic target for the treatment of MASLD.