背景：降糖调脂方改善糖脂代谢紊乱疗效显著，然而，其具体作用机制尚未完全确定。本研究旨在通过网络药理学、分子对接、分子动力学模拟和实验验证，探讨降糖调脂方改善糖脂代谢紊乱的潜在靶点和作用机制。 方法：糖脂代谢紊乱相关靶标来自GeneCards数据库，而降糖调脂方主要活性成分相关作用靶标来自CTD和SwissTarget数据库。使用STRING和Cytoscape构建蛋白质-蛋白质相互作用（PPI）网络。选择潜在关键靶点后，通过Metascape数据库进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析，并构建“药物-成分-靶点-通路”网络图谱。使用AutoDock和PyMOL软件进行分子对接，以验证降糖调脂方的主要成分与核心靶点之间的相关性。对分子对接获得的最佳核心蛋白质-化合物复合物进行分子动力学模拟。建立糖脂代谢紊乱小鼠模型，并通过体内实验验证网络药理学结果。 结果：PPI网络的拓扑分析揭示了TNF、CTNNB1、AKT1、NFKB1、ESR1、FN1、TP53、IL1B、IL6、EGFR等10个核心靶点。GO功能富集分析显示，这些靶点主要与信号转导和转录调控有关。KEGG通路分析表明，这些靶点与脂质和动脉粥样硬化通路相关。分子对接结果表明降糖调脂方的核心活性成分与AKT1、FN1和IL6具有一定的结合亲和力。分子动力学模拟揭示了lovastatin、coptisine、salvianolic acid B和AKT1之间良好的结合能力。动物实验表明，降糖调脂方可能通过下调脂质和动脉粥样硬化通路中AKT1、TP53及炎症因子的表达，并抑制FN1和EGFR的表达，增加CTNNB1和ESR1的表达，从而降低糖脂代谢紊乱小鼠血糖血脂水平，改善糖脂代谢紊乱。 结论：降糖调脂方参与脂质和动脉粥样硬化通路的调节，综合调控糖脂代谢并改善动脉粥样硬化病变，从而防治糖脂代谢紊乱及其并发症的发生发展。

Background: Jiangtang Tiaozhi Formula (JTTZF) is highly effective in improving glycolipid metabolism disorder. However, its exact mechanism of action has not been fully elucidated. Methods: Glycolipid metabolism disorder-related targets were obtained from the GeneCards database, while the relevant action targets of the main active ingredients of JTTZF were obtained from the CTD and SwissTargetPrediction databases. Protein-protein interaction (PPI) networks were constructed using STRING and Cytoscape. After selecting the potential key targets, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed via the Database for Annotation, Visualization and Integrated Discovery (DAVID) database, and a network map of “herb-active ingredient-target-pathway” was constructed. Molecular docking was carried out using AutoDock vina and PyMOL software to verify the correlation between the main components of JTTZF and the core targets. Molecular dynamics simulation was conducted for optimal core protein-compound complexes obtained by molecular docking. A mouse glycolipid metabolism disorder model was established, and the results of network pharmacology were verified by in vivo experiments. Results: Topological analysis of the PPI network revealed ten core targets, including TNF, CTNNB1, AKT1, NFKB1, ESR1, FN1, TP53, IL1B, IL6, and EGFR. GO functional enrichment analysis showed that these targets were mainly related to signal transduction and transcriptional regulation. KEGG pathway analysis showed that these targets were related to lipid and atherosclerosis pathway. Molecular docking results reported that the core active ingredient of JTTZF has a certain binding affinity with AKT1, FN1, and IL6. Molecular dynamics simulations revealed good binding ability between lovastatin, coptisine, salvianolic acid B, and AKT1. Animal experiments showed that JTTZF may reduce blood glucose and blood lipid levels and improve glycolipid metabolism disorder by down-regulating the expression of AKT1, TP53, and inflammatory regulators in lipid and atherosclerotic pathway, inhibiting the expression of FN1 and EGFR, and increasing the expression of CTNNB1 and ESR1. Conclusion: JTTZF participates in the regulation of lipid and atherosclerotic pathway, and comprehensively regulates glucose and lipid metabolism and improves atherosclerotic lesions, thereby preventing and treating the occurrence and development of glycolipid metabolism disorder and its complications.

国家自然科学基金项目（面上项目）（824743233），中国中医科学院科技创新工程项目（CI2021B008）