Ginsenoside F1 as a novel hepatic β3-adrenergic receptor agonist for microbiota-independent cholesterol clearance.

BACKGROUND

Hypercholesterolemia remains a major modifiable risk factor for cardiovascular diseases, calling for innovative strategies to enhance cholesterol clearance beyond conventional approaches. Ginsenoside F1 (GF1), a highly bioavailable ginseng metabolite, shows various pharmacological activities, but its cholesterol-lowering potential remains unclear.

METHODS

The target of GF1 was identified via cellular thermal shift assay, molecular docking, and RNA interference. Downstream signaling cascade was mapped using network pharmacology and inhibitor assays. Quantitative proteomics revealed the pathways by which GF1 regulates cholesterol metabolism, validated both in vitro and in vivo. Finally, the oral bioavailability of GF1 was assessed using pseudo germ-free mice model and liver high-performance liquid chromatography analysis.

RESULTS

Our findings revealed that GF1 directly targeted the hepatic β3-adrenergic receptor (β3-AR) to activate the cAMP/PKA pathway, thereby upregulating SCP2 and CYP7A1 to promote bile acid synthesis and increasing ABCG5/G8 to drive cholesterol excretion. In hypercholesterolemic mice, GF1 demonstrated superior cholesterol-lowering efficacy compared to simvastatin. This effect persisted in germ-free mice, confirming GF1's direct hepatic mechanism of action independent of the gut microbiota following oral administration.

CONCLUSIONS

In this study, we demonstrate that GF1 acts as a potent and selective agonist of β3-AR, promoting cholesterol clearance via a gut microbiota-independent mechanism. These findings provide a molecular basis for the potential application of GF1 in the prevention and treatment of hypercholesterolemia.