Wang_2026_Phytomedicine_157_158295

BACKGROUND: Traditional Chinese medicines (TCMs) demonstrate efficacy in hyperlipidemia prevention and treatment, irrespective of their traditional classifications. However, the molecular mechanisms underlying their hypolipidemic activities remain incompletely defined. This study investigates the lipid-lowering effects and associated mechanisms of three clinically applied TCMs: Citrus reticulata Blanco (Citri Reticulatae Pericarpium, CRP), Nelumbo nucifera Gaertn. (Nelumbinis Folium, NF), Alisma orientale (Sam.) Juzep. (Alismatis Rhizoma, AR). PURPOSE: To compare the molecular mechanisms underpinning the hypolipidemic activities of these three different TCMs. METHODS: Hypolipidemic effects were assessed using palmitic acid (PA) and oleic acid (OA)-stimulated HepG2 cells in vitro and a high-fat diet (HFD)-induced hyperlipidemic mouse model in vivo. Aqueous extracts and hydroalcoholic extracts of each TCM were evaluated. Label-free proteome analysis was used to identify differentially expressed proteins (DEPs) related to lipid metabolism in the hyperlipidemic model. DEPs functions were validated via cellular thermal shift assay, overexpression/knockdown experiments, total cholesterol (TC) and triglyceride (TG) analysis. RESULTS: Hydroalcoholic extracts exhibited superior lipid-lowering efficacy compared to aqueous extracts. Proteomic analysis revealed 270 DEPs. Specific targets associated with each TCM's activity were identified: acyl-CoA dehydrogenase, mitochondrial (ACADSB) for CRP; liver carboxylesterase 1 (CES1) for NF; bile acid-CoA: amino acid N-acyltransferase (BAAT) for AR. Shared targets across all three TCMs included glutathione S-transferase Mu 3 (GSTM3), phosphoenolpyruvate carboxykinase, cytosolic [GTP] (PCK1), ornithine aminotransferase, mitochondrial (OAT), and retinol-binding protein 4 (RBP4). CONCLUSION: CRP, NF, and AR exert hypolipidemic effects through distinct targets (ACADSB, CES1, BAAT, respectively) and shared targets (OAT, GSTM3, PCK1, RBP4), revealing a multi-target regulatory paradigm for TCMs.