泽西银方剂通过调控原癌基因酪氨酸蛋白激酶Src信号通路来改善高脂血症

Abstract

Objective To investigate the therapeutic effects of Zexieyin formula (ZY) on hyperlipidemia (HLP) and elucidate its underlying molecular mechanisms, with a focus on the proto-oncogene tyrosine-protein kinase Src (SRC) signaling pathway. Methods A high-fat diet (HFD)-induced HLP mouse model was established, and mice were treated with ZY (2.57, 5.14, and 10.28 g/kg) or atorvastatin (10 mg/kg) for 6 weeks. SRC overexpression was introduced via tail vein injection of lentivirus. In parallel, a palmitic acid (PA, 250 μM)-induced lipid accumulation model was established in HepG2 cells, followed by ZY treatment (2, 4, and 6 mg/mL) and SRC knockdown or overexpression. Serum lipid profiles (TC, TG, HDL-C, LDL-C), hepatic lipid deposition (Oil Red O, HE staining), and key proteins in lipid metabolism (AMPK/ACC, PPARα, SREBP-1c) and SRC/PI3K/Akt signaling were assessed. Network pharmacology and molecular docking were performed to identify active components and predict core targets. Results ZY treatment, particularly at the medium dose (5.14 g/kg), reduced HFD-induced body weight gain, lowered serum TC and TG, and alleviated hepatic lipid droplet accumulation compared with the Model group (all P  < 0.01). In PA-stimulated HepG2 cells, ZY (6 mg/mL) significantly increased cell viability and reduced TG content (both P  < 0.001). Network pharmacology identified SRC as a core target, and molecular docking showed that quercetin could stably bind to SRC. SRC phosphorylation (Tyr416) was markedly elevated in HFD mouse livers ( P  < 0.01). SRC knockdown significantly reduced lipid droplet accumulation and downregulated SREBP-1c, whereas SRC overexpression partially reversed the protective effects of ZY on serum lipid profiles and hepatic lipid metabolism proteins (all P  < 0.05). Conclusion ZY alleviates HLP and associated hepatic lipid disorders by inhibiting SRC phosphorylation, thereby modulating the AMPK/ACC and SREBP-1c/PPARα pathways to restore lipid metabolic balance. These