Metabolomics and lipidomics combined with network pharmacology to reveal the hypolipidemic mechanism of Hippophae rhamnoides L. flavonoids

• Flavonoids from Hippophae rhamnoides L. reduce TC, TG, and LDL-C and increase HDL-C. • Integrated network pharmacology and omics identify key targets PPARG and MMP9. • FSB modulates PPARG and MMP9, regulating lipid metabolism in hyperlipidemia. Sea buckthorn (SB) is a berry possessing medicinal properties that is rich in flavonoids. Ingestion of SB can inhibit body weight gain, significantly reduce the levels of total cholesterol (TC), triacylglycerols (TG), and low-density lipoprotein cholesterol (LDL-C), and significantly increase the levels of high-density lipoprotein protein cholesterol (HDL-C) in serum and liver of mice. However, the endogenous metabolite and mechanisms through which SB exhibits this lipid-lowering effect remain unclear. This study aimed to explore the lipid-lowering efficacy of SB flavonoids (FSB) and the underlying mechanism using a hyperlipidemia mouse model. The results show that the FSB extract significantly reduced TC, TG, and LDL-C, while increasing HDL-C levels. The FSB extract restored 46 differential lipids and 34 differential metabolites involved in lipid, energy, and amino acid metabolism pathways to normal levels. The compound–target–metabolite network identified six targets closely related to lipid-lowering: PPARA, PPARG, HIF1A, PTGS2, MMP9, and AKT1. Among these, PPARG and MMP9, when bound to various flavonoid compounds, exhibited low binding energies, indicating that they are core targets for FSB. Therefore, FSB primarily influences lipid metabolite levels by regulating PPARG and MMP9 in hyperlipidemic mice. PPARG regulates TGs, diacylglycerol, and arachidonic acid metabolism through β -oxidation and fatty acid synthesis, while MMP9 regulates cholesterol metabolism, affecting hyperlipidemia. This study adopted a comprehensive strategy to explore the lipid-lowering mechanism of FSB for the first time from the perspective of endogenous metabolites and to comprehensively understand the lipid-lowering mechanism of FSB, which provided new insights into dietary interventions for hyperlipidemia and facilitated the development and utilization of SB.