基于网络药理学和加权基因共表达网络探析苓荷颗粒治疗代谢相关脂肪性肝病的潜在靶点和作用机制

Integrating Network Pharmacology and Weighted Gene Co-Expression Network Analysis to Explore the Potential Targets and Mechanism of Linghe Granules in the Treatment of Metabolism Related Fatty Liver Disease

摘要: 目的：探讨名老中医经验方苓荷颗粒治疗代谢相关脂肪性肝病(MAFLD)的潜在靶点和作用机制。方法：通过TCMSP数据库检索出苓荷颗粒所含主要的化学成分；通过TCMID，TCMSP，TCM-PTD，NSTI，SymMap数据库查出中药各成分作用靶标基因；检索Gene Cards，OMIM获得MAFLD相关基因靶点。将获得的苓荷颗粒作用靶点与MAFLD疾病靶点共同输入String数据库，构建药物作用靶点–疾病靶点PPI网络并进行分析。通过核心靶基因筛选及功能富集，最终构建中药–成分–直接靶点–间接靶点-pathway网络。同时，运用GEO数据库下载MAFLD患者RNA-seq高通量测序数据，并进行加权基因共表达网络分析(WGCNA)。结果：构建中药–成分–直接靶点–间接靶点-pathway整体网络，并获得36个潜在活性成分，28个直接靶点。发现TNF信号通路，MAPK信号通路，代谢相关肝病通路等相关通路的关键靶点基因涉及苓荷颗粒作用机制。结合WGCNA分析，找到GGT1，E2F1，LMNA，CDKN1A和IGFBP1 5个基因可能与MAFLD的发生发展密切相关。结论：苓荷颗粒通过TNF信号通路，MAPK信号通路，以及非酒精性肝病相关等生物过程发挥治疗MAFLD的作用；而GGT1、E2F1、LMNA、CDKN1A和IGFBP1是苓荷颗粒治疗MAFLD的潜在靶点。

Abstract: Objective: To explore the potential target and mechanism of Linghe granules in the treatment of metabolic associated fatty liver disease (MAFLD). Methods: The main chemical components of Linghe granules were retrieved by TCMSP database. The target genes of each component were identified by TCMID, TCMSP, TCM-PTD, NSTI, and symMap database. The database Genecards and OMIM were used to obtain the MAFLD related target genes. The targets of Linghe granules and MAFLD related targets were input into the String database to construct PPI network. After network analysis, core target genes were selected, of which functional enrichment analysis was performed. Based on the precious results, Linghe granules-component-direct target-indirect target-pathway network was constructed. Meanwhile, the high-throughput RNA-seq sequencing data of MAFLD patients were downloaded from the GEO database and analyzed by weighted correlation network analysis (WGCNA). Results: Thirty-six potential active components and 28 direct targets were obtained. The enriched pathways of Linghe granules related target genes include TNF signaling pathway, MAPK signaling pathway, and nonalcoholic liver disease. Integrated with WGCNA analysis, five genes, GGT1, E2F1, LMNA, CDKN1A and IGFBP1, were found to be closely associated with the occurrence and development of MAFLD. Conclusion: TNF signaling pathway, MAPK signaling pathway, and non-alcoholic liver disease biological processes are related to Linghe granules treating MAFLD. GGT1, E2F1, LMNA, CDKN1A and IGFBP1, are potential targets of Linghe granules in the treatment of MAFLD.