Abstract

Background Nonalcoholic fatty liver disease (NAFLD) is a significant underlying driver of hepatocellular carcinoma; however, current clinical treatment options remain limited. Ginsenoside CK (CK), a natural bioactive compound, has shown promise in modulating lipid metabolism and protecting liver function. Nevertheless, its therapeutic potential against the pathogenesis of NAFLD and the associated molecular pathways is not fully understood. This study employed an integrated strategy that combines transcriptomic analysis with both in vivo and in vitro validation, utilizing a high-fat diet (HFD)-induced rat model to elucidate the efficacy and molecular mechanisms of CK in ameliorating NAFLD. Methods An NAFLD rat model was established through HFD feeding to assess the effects of CK on various physiological and biochemical parameters, thereby clarifying its role in regulating lipid metabolism and providing hepatoprotection in vivo. Additionally, a free fatty acid (FFA)-induced Huh7 cell model was constructed to evaluate the in vitro activity of CK in promoting lipid metabolism and inhibiting lipid accumulation. Subsequently, transcriptomic analysis was conducted to identify potential targets and elucidate the mechanisms underlying the effects of CK. Finally, the proposed mechanism was verified through in vivo experiments. Results In vivo results indicated that CK treatment significantly mitigated the increases in body weight and organ indices induced by a HFD. Additionally, CK improved biochemical parameters in both liver and serum, alleviated liver injury, steatosis, and insulin resistance, thereby providing a protective effect on liver tissue. Furthermore, CK markedly reduced the deposition of intracellular lipid droplets in hepatocytes. It also enhanced the expression of fatty acid metabolism-related genes, CPT1 and CPT2, in the liver, while downregulating the expression of lipogenic genes, including ACC1, FAS, and SREBP1c. Mechanistic investigations revealed that CK