<i>Panax notoginseng</i> Saponins Ameliorate High‐Fat Diet‐Induced Liver Injury via Mechanisms Involving <scp>TLR4</scp> ‐Mediated Signaling and Lipid Metabolism

<i>Panax notoginseng</i> saponins (PNS), the primary bioactive constituents derived from the traditional herb <i>Panax notoginseng</i>, have been used in nutritional supplements. However, their molecular mechanisms against hyperlipidemia-induced liver injury remain to be fully elucidated. In this study, supplementation with PNS (200 mg/kg diet) for 12 weeks significantly ameliorated high-fat diet (HFD)-induced liver injury in C57BL/6J mice, as evidenced by improved serum lipid profiles and attenuated hepatic oxidative stress and inflammation. Lipidomics analysis indicated that PNS administration restored hepatic lipid homeostasis, particularly by normalizing dysregulated triglycerides. Mechanistically, PNS markedly suppressed the activation of key inflammatory signaling pathways, including both the TLR4/MyD88-mediated NF-κB and MAPK (ERK, JNK, p38) cascades. Complementary in vitro experiments in LPS-stimulated HepG2 cells confirmed that PNS attenuated cellular injury and downregulated these pathways. Notably, the protective effect of PNS was not additive to that of the specific TLR4 inhibitor TAK-242, indicating a functional convergence on the TLR4 signaling axis. Collectively, these findings demonstrate that PNS protects against HFD-induced liver injury by improving lipid metabolism and attenuating hepatic inflammation via mechanisms involving the suppression of TLR4-mediated NF-κB and MAPK signaling, providing a refined mechanistic basis for its application as a dietary supplement in metabolic liver health.