目的 利用网络药理学及分子对接技术探讨白藜芦醇治疗乙型病毒性肝炎相关性肝癌的作用机制。方法 运用Swiss Target Prediction和Target Net数据库预测白藜芦醇的潜在作用靶点；检索GeneCards、OMIM、DisGeNET数据库获取乙型病毒性肝炎相关性肝癌的靶点信息；通过Venny图得到白藜芦醇与乙型病毒性肝炎相关性肝癌的交集靶点。运用STRING数据库构建交集靶点的PPI网络；使用Cytoscape软件进行网络拓扑分析筛选关键靶点；利用Metascape数据库对交集靶点进行基因本体（GO）和京都基因组百科全书（KEGG）通路分析；通过Cytoscape建立“药物–靶点–通路”网络探究白藜芦醇治疗乙型病毒性肝炎相关性肝癌的潜在作用机制。最后通过分子对接明确白藜芦醇与关键靶点的作用机制。结果 预测得到白藜芦醇靶点496个，筛选、去重得到疾病靶点1 018个，最后得到交集靶点48个。排名前10位的关键靶点分别为肿瘤坏死因子（TNF）、基质金属蛋白酶9（MMP9）、表皮生长因子受体（EGFR）、B淋巴细胞瘤-2（Bcl-2）、趋化因子C-X-C-基元受体4（CXCR4）、热休克蛋白90α家族A类成员1（HSP90AA1）、热休克蛋白90α家族B类成员1（HSP90AB1）、前列腺素内过氧化物合酶2（PTGS2）、酪氨酸激酶受体（KDR）、雌激素受体α（ESR1）。GO和KEGG富集分析主要指向磷代谢过程、细胞迁移等功能，参与的信号传导通路主要包括癌症中的通路、脂质与动脉粥样硬化、趋化因子信号通路、白细胞介素（IL）-17信号通路、糖尿病并发症中的晚期糖基化终末产物–晚期糖基化终末产物受体（AGE-RAGE）信号通路；低氧诱导因子（HIF）-1信号通路等。分子对接结果显示白藜芦醇与关键靶点对接结合能均小于0。结论 白藜芦醇可能通过TNF、Bcl-2、CXCR4、EGFR等多个靶点，从而调节AGE-RAGE信号通路、IL-17信号通路等多条信号通路，进而抑制肿瘤细胞增殖、抑制肿瘤血管生成、促进肿瘤细胞凋亡等来发挥治疗乙型病毒性肝炎相关性肝癌的作用。

Objective To explore the mechanism of resveratrol in treatment of hepatitis B virus-related liver cancer by using network pharmacology and molecular docking technology. Methods Swiss Target Prediction and Target Net database were used to predict the potential targets of resveratrol. GeneCards, OMIM, and DisGeNET database were searched to obtain the target information of hepatitis B-related liver cancer. The intersection targets of resveratrol and hepatitis B-related liver cancer were obtained by Venny diagram. PPI network of intersection targets was constructed by STRING database. Cytoscape software was used for network topology analysis to screen key targets. GO enrichment analysis and KEGG pathway analysis were performed on the intersection targets using the Metascape database.“Drug-target-pathway” network was established by Cytoscape to explore the potential mechanism of resveratrol in treatment of hepatitis B-related liver cancer. Mechanism of action of resveratrol and key targets was further clarified by molecular docking. Results A total of 496 resveratrol targets were predicted, 1 018 disease targets were obtained by screening and deduplication, and 48 intersection targets were finally obtained. The top 10 key targets were TNF, MMP9, EGFR, Bcl-2, CXCR4, HSP90AA1, HSP90AB1, PTGS2, KDR, and ESR1. GO and KEGG enrichment analysis mainly focused on phosphorus metabolism, cell migration and other functions. The signal transduction pathways involved mainly included pathways in cancer, lipids and atherosclerosis, chemokine signaling pathway, IL-17 signaling pathway, AGE-RAGE signaling pathway in diabetic complications, HIF-1 signaling pathway, etc. Results of molecular docking showed that the binding energy of resveratrol to key targets was less than 0. Conclusion Resveratrol may regulate AGE-RAGE signaling pathway, IL-17 signaling pathway and other signaling pathways through multiple targets such as TNF, Bcl-2, CXCR4, EGFR, etc. Thereby inhibiting tumor cell proliferation, inhibiting tumor angiogenesis, and promoting tumor cell apoptosis to play a role in treatment of hepatitis B-related liver cancer.

R285

武汉市知识创新专项项目-曙光计划项目（2023020201020406）