目的 采用网络药理学结合GEO数据库多芯片联合分析及分子对接的方法研究化橘红防治动脉型肺动脉高压的潜在分子作用机制。方法 利用TCMSP、ETCM、Swiss Target Prediction和PharmMapper等数据库结合文献报道，获取化橘红活性成分的作用靶点。通过GEO数据库多芯片联合分析获得动脉型肺动脉高压的差异表达基因，联合GeneCard、DisGeNET和DiGSeE等数据库筛选出动脉型肺动脉高压的潜在疾病基因。对疾病基因和活性成分靶点取交集，以Cytoscape 3.7.2软件构建化橘红活性成分–靶点的可视化网络。基于String数据库，构建化橘红防治动脉型肺动脉高压靶点的蛋白互作（PPI）网络，分析筛选出核心靶点，进行基因本体（GO）功能富集分析和京都基因与基因组百科全书（KEGG）信号通路富集分析，构建化橘红活性成分–靶点–信号通路网络。将化橘红主要活性成分与网络拓扑分析后所得到的排名前10的核心靶点进行分子对接，Autodock Vina预测其分子结合自由能及Pymol作分子对接可视化图。结果 筛选出活性成分15个，得到可作用于动脉型肺动脉高压的靶点150个，核心靶点涉及肿瘤蛋白P53（TP53）、β-肌动蛋白（ACTB）、肿瘤坏死因子（TNF）、血管内皮生长因子A（VEGFA）、丝裂原活化蛋白激酶3（MAPK3）、缺氧诱导因子-1α（HIF1A）和胱天蛋白酶3（CASP3）等。GO富集分析得到生物学过程相关条目572条、分子功能相关条目115条及细胞组分相关条目84条（P<0.01）。KEGG通路富集分析得到173条信号通路（P<0.01），主要涉及癌症通路、脂质与动脉粥样硬化通路、流体剪切应力与动脉粥样硬化、细胞衰老、缺氧诱导因子-1（HIF-1）信号通路、磷酯酰肌醇-3-激酶（PI3K）-蛋白激酶B（Akt）信号通路、白细胞介素-17（IL-17）信号通路和细胞凋亡等。分子对接结果表明关键成分和关键靶点间均具有较好的结合活性。结论 化橘红通过多靶点、多通路发挥治疗动脉型肺动脉高压的作用。

Objective To investigate the potential molecular mechanism of action of Citri Grandis Exocarpium in the prevention and treatment of pulmonary arterial hypertension by using network pharmacology combined with GEO database multi-chip analysis and molecular docking method. Methods TCMSP, ETCM, Swiss Target Prediction, PharmMapper and other databases were used to obtain the targets of the active ingredients of Citri Grandis Exocarpium in combination with literature reports. The differentially expressed genes of arterial pulmonary hypertension were obtained by multi-chip analysis of GEO database, and the potential disease genes of arterial pulmonary hypertension were screened by combining with GeneCard, DisGeNET, and DiGSeE databases. The intersection of the disease genes and the active ingredient targets was taken, and the Cytoscape 3.7.2 software was used to construct the visualization network of the active ingredient-targets of Citri Grandis Exocarpium. Based on the String database, the protein interactions network of the targets of Citri Grandis Exocarpium for the prevention and treatment of arterial pulmonary hypertension was constructed, the core targets were analyzed and screened, GO functional enrichment analysis and KEGG signaling pathway enrichment analysis were performed, and the active ingredient-target-signaling pathway network of Citri Grandis Exocarpium was constructed. The molecular docking was performed between the top ten active ingredients and the core targets obtained from the network topology analysis, and the molecular binding free energy was predicted by Autodock Vina and visualized by Pymol. Results 15 active ingredients were screened, and 150 targets were identified for arterial pulmonary hypertension, including TP53, ACTB, TNF, VEGFA, MAPK3, HIF1A, CASP3, etc. GO enrichment analysis yielded 572 entries related to biological processes, 115 entries related to molecular functions, and 84 entries related to cellular components (P < 0.01). KEGG pathway enrichment analysis yielded 173 signaling pathways (P < 0.01), mainly involving cancer pathway, lipid and atherosclerosis pathway, fluid shear stress and atherosclerosis, cellular senescence, HIF-1 signaling pathway, PI3K-Akt signaling pathway, IL-17 signaling pathway, and apoptosis. The molecular docking results showed good binding activity between key components and key targets. Conclusion Citri Grandis Exocarpium exerts its effect on the treatment of arterial pulmonary hypertension through multi-target and multi-pathway.

R925.5

国家自然科学基金面上项目（81370242）；广东医科大学学科建设项目（4SG21229GDGFY01）；广东医科大学校级大学生创新创业训练计划项目（GDMU2021117，GDMU2021156）；湛江市非资助科技攻关计划项目（2021B01145）；湛江市科技计划项目（2022A01183）