基于网络药理学和分子对接探讨越鞠丸治疗代谢功能障碍相关脂肪性肝病作用机制

Study on the Mechanism of Yueju Pill in the Treatment of Metabolic Dysfunction-Associated Steatotic Liver Disease Based on Network Pharmacology and Molecular Docking

摘要: 目的：基于网络药理学和分子对接技术探讨越鞠丸治疗代谢功能障碍相关脂肪性肝病(MASLD)的潜在作用靶点及分子机制。方法：通过文献整理，收集越鞠丸的入血成分，通过SwissTargetPrediction数据库预测成分的作用靶点，通过GeneCards数据库检索代谢功能障碍相关脂肪性肝病相关靶点，并进行筛选。入血成分靶点与疾病靶点取交集使用Cytoscape 3.5.0软件构建“成分–靶点–疾病”网络关系图，并利用DAVID数据库对交集靶点进行GO和KEGG富集分析。使用STRING数据库获得蛋白质–蛋白质互作(PPI)信息，构建PPI网络，以度中心性、中介中心性、接近中心性筛选出越鞠丸治疗MASLD的关键靶点，采用CB-Dock2在线平台对关键成分与关键靶点进行分子对接验证。结果：筛选后得越鞠丸有效成分共32个，药物作用靶点601个，MASLD相关靶点1189个，药物与疾病交集靶点183个；富集分析表明这些靶点显著富集于凋亡过程的调控、PI3K/AKT信号通路、MAPK信号通路等154条通路，蛋白互作网络分析提示TNF、AKT1、TP53、STAT3、JUN、EGFR、HIF1A、NFKB1可能为关键靶点，分子对接结果显示关键成分与关键靶点结合能都小于−5.0 kcal/mol，整体对接结果较好。结论：通过网络药理学证明越鞠丸对防治MASLD具有多成分、多靶点的特点，为进一步的机制研究及临床应用提供了依据。

Abstract: Objective: To explore the potential therapeutic targets and molecular mechanisms of Yueju Pill in treating metabolic dysfunction-associated steatotic liver disease (MASLD) based on network pharmacology and molecular docking technology. Methods: The blood-entering components of Yueju Pill were collected through a literature review. The SwissTargetPrediction database was used to predict the targets of these components, and the GeneCards database was used to retrieve MASLD-related targets, followed by screening. The intersection targets between the component targets and disease targets were identified and used to construct a “Component-Target-Disease” network diagram using Cytoscape 3.5.0 software. GO and KEGG enrichment analyses of the intersection targets were performed using the DAVID database. Protein-protein interaction (PPI) information was obtained from the STRING database to construct a PPI network. Degree centrality, betweenness centrality, and closeness centrality were calculated to screen for the key targets of Yueju Pill against MASLD. Molecular docking verification between the key components and key targets was conducted using the CB-Dock2 online platform. Results: A total of 32 active components of Yueju Pill were screened, corresponding to 601 drug-related targets and 1189 MASLD-related targets. There were 183 intersection targets between the drug and the disease. Enrichment analysis indicated that these targets were significantly enriched in 154 pathways, including the regulation of the apoptotic process, PI3K/AKT signaling pathway, and MAPK signaling pathway. PPI network analysis suggested that TNF, AKT1, TP53, STAT3, JUN, EGFR, HIF1A, and NFKB1 might be the key targets. Molecular docking results showed that the binding energies between the key components and key targets were all less than −5.0 kcal/mol, indicating good overall docking performance. Conclusion: This network pharmacology study demonstrates that Yueju Pill exhibits multi-component and multi-target characteristics in the prevention and treatment of MASLD, providing a basis for further mechanistic research and clinical application.