Integrated Transcriptomic and Metabolomic Approaches Reveal the Protective Effect of 10-HDA on MASLD via AMPK-Dependent Cholesterol Metabolism

The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and the limited treatment options highlight the need for effective alternatives. Natural bioactive compounds are increasingly valued for their safety and multifunctional regulatory effects. 10-hydroxy-2(E)-decenoic acid (10-HDA), a unique fatty acid from royal jelly, exhibits diverse biological activities and potential benefits for liver health. In this study, we investigated the hepatoprotective effects of 10-HDA and its underlying mechanisms using palmitic acid/oleic acid-treated HepG2 cells and high-fat diet-induced golden hamsters. 10-HDA significantly reduced hepatic triglyceride and cholesterol contents, improved serum lipid profiles, and alleviated steatosis. Integrated transcriptomic and metabolomic analysis revealed 10-HDA regulates lipid homeostasis mainly through activating AMPK signaling and regulating cholesterol metabolism, including downregulation of   HMGCR, SORT1, and SOAT1, and upregulation of ABCG5/8 and CYP7A1. AMPKα knockdown abolished these effects, confirming its key role in mediating the metabolic benefits of 10-HDA.  These findings demonstrate that10-HDA protects against MASLD by modulating hepatic cholesterol metabolism via AMPK activation, highlighting its potential as a dietary bioactive compound for metabolic health.