Non-alcoholic fatty liver disease (NAFLD) is a series of disorders of liver metabolism caused by the accumulation of lipids in the liver, which is considered the main cause of hepatocellular carcinoma. Our previous study demonstrated the promising efficacy of ginsenoside Rh4 in improving the intestinal tract and its related metabolites. Meanwhile, many studies in the literature have investigated the gut microbiota and its metabolites, such as bile acids (BAs) and short-chain fatty acids (SCFAs), which play a key role in the pathogenesis of NAFLD. Therefore, this study focused on whether Rh4 could achieve therapeutic effects on NAFLD through the gut–liver axis. The results showed that Rh4 exhibited sound therapeutic effects on the NAFLD model induced by the Western diet and CCl₄ in mice. In the liver, the degrees of hepatic steatosis, lobular inflammation levels, and bile acid in the liver tissue were improved after Rh4 treatment. At the same time, Rh4 treatment significantly increased the levels of intestinal SCFAs and BAs, and these changes were accompanied by the complementary diversity and composition of intestinal flora. In addition, correlation analysis showed that Rh4 affected the expression of proteins involved in the farnesoid X receptor (FXR) signaling pathway in the liver and intestine, which modulates hepatic lipid metabolism, inflammation, and proteins related to bile acid regulation. In conclusion, our study provides a valuable insight into how Rh4 targets the gut–liver axis for the development of NAFLD, which indicates that Rh4 may be a promising candidate for the clinical therapy of NAFLD.

Hepatocellular carcinoma (HCC) is one of the most prevalent and deadly cancers in the world. Recently, suppression of glutamine metabolism has become one of the hottest therapy targets for cancer treatment. There is a growing amount of research that indicates that ginsenosides possess good anti-tumor activity. However, the effect of ginsenoside Rk1 on glutamine metabolism in HCC is unclear. In this study, Rk1 was demonstrated to be effective at inhibiting the proliferation of HCC through the induction of cell cycle arrest and apoptosis. Especially, Rk1 was shown for the first time to inhibit glutamine metabolism in HCC. Rk1 downregulates GLS1 expression, and consequently decreases the GSH production, stimulating ROS accumulation to induce apoptosis. In addition, transcriptomic results showed that the ERK/c-Myc signaling pathway was enriched in HepG2. Rk1 exerts an inhibitory effect on glutamine metabolism in HCC by regulating the ERK/c-Myc signaling pathway, and inducing apoptosis in vitro and in vivo with less toxicity. Therefore, ginsenoside Rk1 could be a promising candidate for the clinical treatment of HCC.