Sea buckthorn polyphenols ameliorate insulin resistance: Insights from metabolomics and network pharmacology

Sea buckthorn polyphenols (SBPs) have been reported to alleviate insulin resistance (IR), but their key bioactive compounds and underlying mechanisms remain unclear. In this study, 48 phenolics were annotated from four sea buckthorn varieties. SBPs improved glucose consumption and glycogen synthesis in IR-HepG2 cells, with MON showing the most pronounced effect. Correlation analysis suggested positive associations between several phenolics, including isorhamnetin, kaempferol, quercetin, eriodictyol, and catechin, and cellular glucose metabolism-related indicators. Network pharmacology identified these compounds as representative candidates associated with IR-related targets, including JNK, IRS-1, PI3K, and AKT. Molecular docking further suggested favorable predicted binding affinities between candidate phenolics and selected targets, with isorhamnetin showing relatively strong predicted affinity and cellular activity. Therefore, isorhamnetin was selected as a representative key candidate for mechanistic validation. Mechanistically, isorhamnetin reduced inflammatory and oxidative stress responses, modulated the JNK/IRS-1/PI3K/AKT signaling pathway, promoted glycogen synthesis, suppressed gluconeogenesis, and improved glucose utilization in IR-HepG2 cells. These findings provide preliminary in vitro evidence that isorhamnetin-rich SBPs may serve as promising dietary candidates for improving IR-related glucose metabolic dysfunction.