Ginsenoside Rb3 Combined with 20(S)-Protopanaxadiol Ameliorates Hypercholesterolemia via the Regulation of Lipid Metabolism and Gut Microbiota

Abstract Hypercholesterolemia is a major contributor to cardiovascular disease and imposes a serious global disease burden. The stems and leaves of Panax notoginseng, as edible parts of the plant, are rich in ginsenoside Rb3. However, the lipid-lowering effects and mechanism of ginsenoside Rb3 remain unclear, which limits the utilization of Panax notoginseng stems and leaves. Our results showed that ginsenoside Rb3, particularly with PPD, inhibited cholesterol absorption, enhanced LDLR-mediated LDL uptake, reduced body weight, alleviated dyslipidemia, and attenuated liver injury and lipid accumulation. These enhanced effects are supported by direct regulation of intestinal and hepatic lipid metabolism targets (especially NPC1L1 and PCSK9), together with restoration of gut microbiota homeostasis. Molecular docking and dynamic simulations further confirmed the stable binding of ginsenoside Rb3 plus PPD to these proteins. Our findings demonstrate the improvement of ginsenoside Rb3 alone or combined with PPD on cholesterol metabolism and support the targeted development of Panax notoginseng stems and leaves.