目的 基于网络药理学与分子对接技术探讨地骨皮调血脂的作用机制。方法 使用TCMSP数据库并查阅相关文献确定地骨皮活性成分；采用SwissTargetPrediction、GeneCard和OMIM数据库预测地骨皮活性成分靶点和高脂血症相关靶点，应用Venny 2.1取两者交集；运用Cytoscape 3.8.2软件绘制成分-靶点-疾病网络；应用String数据库构建交集靶点的蛋白质-蛋白质相互作用（protein-protein interaction，PPI）网络；将交集靶点输入Metascape数据库进行基因本体（gene ontology，GO）功能及京都基因与基因组百科全书（Kyoto encyclopedia of genes and genomes，KEGG）通路富集分析，利用Cytoscape 3.8.2软件绘制地骨皮活性成分-靶点-通路网络，预测其调血脂作用机制；采用分子对接和细胞实验进一步探究地骨皮的调血脂作用机制。结果 共筛选出地骨皮潜在活性成分14个以及153个交集靶点；GO功能和KEGG通路分析发现主要涉及过氧化物酶体增殖物激活受体（peroxisome proliferator activated receptor，PPAR）信号通路、AMP激活的蛋白激酶（AMP-activated protein kinase，AMPK）信号通路、脂质和动脉粥样硬化、胰岛素抵抗、脂肪消化吸收以及胆汁分泌等。分子对接结果显示，地骨皮中金合欢素、蒙花苷、β-谷甾醇以及大黄素等活性成分与关键靶蛋白之间具有良好的结合作用。细胞实验结果显示，蒙花苷、β-谷甾醇以及大黄素均能够抑制油酸诱导的人肝癌HepG2细胞脂质蓄积（P＜0.05、0.01）。Western blotting实验结果显示，蒙花苷和大黄素均能上调人结肠腺癌Caco-2细胞中腺苷三磷酸结合盒转运蛋白A1（ATP binding cassette transport protein A1，ABCA1）蛋白表达（P＜0.05、0.01）。结论 地骨皮中的蒙花苷、大黄素、β-谷甾醇等活性成分可能是通过作用于PPARα、PPARγ等靶点干预PPAR和AMPK等信号通路，影响下游蛋白ABCA1的表达，抑制细胞中的脂质蓄积从而发挥调血脂作用。

Objective To explore the mechanism of hypolipidemic effect of Digupi (Lycii Cortex) based on network pharmacology and molecular docking technology. Methods The active ingredients were determined by Using TCMSP database and browsing literatures. SwissTargetPrediction, GeneCard and OMIM databases were used to predict the active component targets of Lycii Cortex and hyperlipidemia-related targets, and Venny 2.1 was used to obtain intersection targets. Cytoscape 3.8.2 software was used to map the component-intersection targets-disease network. Protein-protein interaction (PPI) network with intersecting targets was constructed by String database. The intersection targets were input into Metascape databases for gene ontology (GO) function and Kyoto encyclopedia of geneses and genomes (KEGG) pathway enrichment analysis to predict its possible hypolipidemic mechanism, the diagram of components-intersection target-pathway of Lycii Cortex were showing by Cytoscape 3.8.2 software. Molecular docking and cell experiments were used to further explore the hypolipidemic mechanism of Lycii Cortex.Results A total of 14 potential active components and 153 intersecting targets were obtained from Lycii Cortex. GO function and KEGG pathway analysis showed that the key targets involved AMP-activated protein kinase (AMPK) signaling pathway, peroxisome proliferator activated receptor (PPAR) signaling pathway, lipid and atherosclerosis, insulin resistance, fat digestion and absorption, bile secretion, etc. The molecular docking results showed that the active components of acacetin, linarin, β-sitosterol and emodin displayed strong binding abilities with key targets respectively. In addition, results of cell experiments in vitro showed that linarin, β-sitosterol and emodin could inhibit lipid accumulation in oleic acid-induced HepG2 cells (P < 0.05, 0.01). Western blotting experiments results showed that linarin and emodin could increase ATP binding cassette transport protein A1 (ABCA1) protein expression in Caco-2 cells (P < 0.05, 0.01). Conclusion The active components in Lycii Cortex such as linarin, emodin and β-sitosterol may act on PPARα, PPARγ and other targets, inhibit the lipid accumulation, increase the expression of ABCA1 through PPAR signaling pathway, AMPK signaling pathway and other related pathways, thereby exerting a hypolipidemic effect.

R285.5

国家自然科学基金资助项目（81673693）；中药抗炎机制与智能制造研究创新能力建设项目（20201178）