基于网络药理学的不同方法炮制的何首乌肝毒性机制探讨及实验验证

目的 基于网络药理学及实验验证探讨制首乌肝毒性的机制。方法 利用中药系统药理学数据库与分析平台（TCMSP）、中医药整合药理学研究平台（TCMIP v2.0）收集制首乌的活性成分和作用靶点。通过GeneCards和OMIM数据库获取肝损伤相关的靶点。用Venny图筛选获得两者的共同靶标后，利用STRING数据库进行蛋白质相互作用（PPI）网络分析，用Cytoscape软件构建药物-成分-靶点网络，并且利用R语言进行基因本体论（GO）富集分析和京都基因与基因组百科全书（KEGG）通路富集。利用体内实验进一步验证何首乌不同炮制品的肝毒性。结果 分别获取制首乌活性成分30个，肝毒性相关靶点527个，制首乌活性成分与肝损伤的共同靶点48个，包括JUN、MAPK1、CYP3A4等。KEGG通路分析筛选了135条相关信号通路，显示非酒精性脂肪肝通路和TNF信号通路等可能在制首乌肝毒性中起关键作用。体内实验表明，炮制后的何首乌肝毒性有效减轻，以九蒸九晒法效果最好。结论 制首乌肝毒性具有多成分、多靶点、多通路协同作用的特点，九蒸九晒法制首乌引起肝毒性的程度最轻。

Discussion and experimental verification of hepatotoxicity mechanism of Polygonum multiflorum processed by different methods based on network pharmacology

Objective To explore the mechanism of hepatotoxicity of Radix Polygoni Multiflori Preparata based on network pharmacology and experimental verification. Methods The active components and action targets of Radix Polygoni Multiflori Preparata were collected by using the systematic pharmacology analysis platform of traditional Chinese medicine (TCMSP), and the integrated pharmacology research platform of traditional Chinese medicine (TCMIP). Liver injury related targets were obtained through Genecards and OMIM databases. After the common targets were screened by Venny diagram, PPI analysis was carried out by STRING database, the drug-component-target network was constructed by Cytoscape software, and GO enrichment analysis and KEGG pathway analysis were carried out by R language. Finally, the above results were further verified by in vivo experiments. Results 30 active components of Radix Polygoni Multiflori Preparata, and 527 hepatotoxicity related targets were obtained, and 48 common targets of Radix Polygoni Multiflori Preparata and liver injury were collected, including JUN, MAPK1, CYP3A4, etc. KEGG pathway analysis screened 135 related signal pathways, indicating that nonalcoholic fatty liver pathway and TNF signal pathway may play a key role in the hepatotoxicity of Radix Polygoni Multiflori Preparata. In vivo experiments showed that processed Radix Polygoni Multiflori could effectively reduce the hepatotoxicity of Radix Polygoni Multiflori, and the effect of processing of steamed for nine times and shined for nine times was the best. Conclusion Hepatotoxicity of Radix Polygoni Multiflori Preparata has the characteristics of multi-component, multi-target and multi-channel synergy, which provides a theoretical basis for the further study of the complex mechanism of hepatotoxicity of Radix Polygoni Multiflori.