Discovery of farnesoid X receptor antagonists from Salvia miltiorrhiza based on virtual screening and activity verification.

The farnesoid X receptor (FXR) is a promising therapeutic target for the treatment of non-alcoholic fatty liver disease (NAFLD). Salvia miltiorrhiza, a traditional Chinese medicine, has demonstrated significant efficacy in the prevention and treatment of liver diseases. Consequently, investigating the potential effects of Salvia miltiorrhiza on FXR could provide new insights for NAFLD treatment. This study explores whether active ingredients from Salvia miltiorrhiza can target FXR and serve as therapeutic agents for treating NAFLD. The findings revealed that cynaroside and lithospermic acid displayed strong FXR antagonistic activity, with IC50 values of 5.41 ± 1.08 μM and 16.92 ± 2.68 μM, respectively. Salvianolic acid A also showed moderate activity (IC50 = 56.35 ± 4.54 μM). MTT assays demonstrated that these three compounds were non-toxic to HepG2 and LO2 cells at a concentration of 200 μM. Molecular dynamics simulations were conducted to elucidate the interaction mechanisms of cynaroside and lithospermic acid with FXR. These results suggest that cynaroside and lithospermic acid from Salvia miltiorrhiza may be potential candidates for targeting FXR in treating NAFLD.