Abstract

Background The formation of foam cells (FCs) is the major contributor to the development of atherosclerosis (AS). Gynostemma pentaphyllum is widely used to treat AS and exhibits biological activity against FCs formation. Narcissoside (Nar) is an important component from G. pentaphyllum flavonoids. This study aimed to reveal the beneficial effect and underlying mechanism of Nar on inhibiting the formation of FCs in AS. Methods The inhibitory effects of Nar on FCs formation were evaluated using Oil Red O staining and flow cytometry in ox-LDL-stimulated THP-1 and BMDMs. High-fat diet (HFD)-induced ApoE −/− mice were administered Nar for 9 weeks to assess its therapeutic efficacy in treating AS. Luciferase reporter gene assays, Western blot, and RT-qPCR were performed to investigate the mechanisms of action of Nar, which were further confirmed through in vitro experiments using siRNA of NR4A1 for reverse validation. Results In vitro, Nar attenuated FCs formation as evidenced by reduced intracellular lipid levels and ox-LDL uptake rates. In vivo, Nar effectively improved lipid profiles and serum inflammatory factors. Histological analysis showed that Nar reduced the area of the necrotic core and lipid accumulation in the aortic roots. Mechanistically, Nar inhibited CD36 transcription by enhancing the expression and nuclear translocation of NR4A1. Mutation of the NR4A1 binding site within the CD36 promoter abolished the inhibitory effect of Nar. Additionally, silencing NR4A1 eliminated Nar’s capacity to suppress ox-LDL uptake and downregulate CD36 expression. Conclusions Nar attenuated AS by inhibiting CD36-mediated FCs formation through upregulating the expression and nuclear translocation of NR4A1, highlighting it as a promising therapeutic candidate for AS.