Astragaloside IV improves MASLD via GCN5-LXRα/SREBP1c signaling pathway-mediated hepatic de novo lipogenesis

Abstract Background Astragaloside IV (AS-IV), a bioactive saponin from Astragalus membranaceus, shows promise for treating metabolic dysfunction-associated steatotic liver disease (MASLD), though its mechanisms remain unclear. Purpose This study aimed to elucidate how AS-IV alleviates hepatic steatosis, specifically investigating its epigenetic regulation of lipogenesis. Methods Using high-fat diet-fed mice and lipids-loaded hepatocytes, we assessed AS-IV's effects through SREBP-1c overexpression, histone acetylation analysis, and GCN5 rescue experiments. Results AS-IV significantly reduced hepatic steatosis by suppressing SREBP-1c-mediated de novo lipogenesis. Mechanistically, it inhibited histone acetyltransferase GCN5, decreasing H3K9/H3K14 acetylation at the SREBP-1c promoter and attenuating LXRα-driven transcription. GCN5 overexpression reversed AS-IV's suppression of SREBP-1c and lipid accumulation. Conclusion AS-IV uniquely downregulates GCN5 expression at the transcriptional level, exerting epigenetic regulation to disrupts lipogenic programming, This represents a novel multi-target approach against MASLD that connects natural product pharmacology with epigenetic modulation.