目的 利用網(wǎng)絡(luò)藥理學(xué)及分子對接技術(shù)探討白藜蘆醇治療乙型病毒性肝炎相關(guān)性肝癌的作用機制。方法 運用Swiss Target Prediction和Target Net數(shù)據(jù)庫預(yù)測白藜蘆醇的潛在作用靶點；檢索GeneCards、OMIM、DisGeNET數(shù)據(jù)庫獲取乙型病毒性肝炎相關(guān)性肝癌的靶點信息；通過Venny圖得到白藜蘆醇與乙型病毒性肝炎相關(guān)性肝癌的交集靶點。運用STRING數(shù)據(jù)庫構(gòu)建交集靶點的PPI網(wǎng)絡(luò)；使用Cytoscape軟件進行網(wǎng)絡(luò)拓撲分析篩選關(guān)鍵靶點；利用Metascape數(shù)據(jù)庫對交集靶點進行基因本體（GO）和京都基因組百科全書（KEGG）通路分析；通過Cytoscape建立“藥物–靶點–通路”網(wǎng)絡(luò)探究白藜蘆醇治療乙型病毒性肝炎相關(guān)性肝癌的潛在作用機制。最后通過分子對接明確白藜蘆醇與關(guān)鍵靶點的作用機制。結(jié)果 預(yù)測得到白藜蘆醇靶點496個，篩選、去重得到疾病靶點1 018個，最后得到交集靶點48個。排名前10位的關(guān)鍵靶點分別為腫瘤壞死因子（TNF）、基質(zhì)金屬蛋白酶9（MMP9）、表皮生長因子受體（EGFR）、B淋巴細胞瘤-2（Bcl-2）、趨化因子C-X-C-基元受體4（CXCR4）、熱休克蛋白90α家族A類成員1（HSP90AA1）、熱休克蛋白90α家族B類成員1（HSP90AB1）、前列腺素內(nèi)過氧化物合酶2（PTGS2）、酪氨酸激酶受體（KDR）、雌激素受體α（ESR1）。GO和KEGG富集分析主要指向磷代謝過程、細胞遷移等功能，參與的信號傳導(dǎo)通路主要包括癌癥中的通路、脂質(zhì)與動脈粥樣硬化、趨化因子信號通路、白細胞介素（IL）-17信號通路、糖尿病并發(fā)癥中的晚期糖基化終末產(chǎn)物–晚期糖基化終末產(chǎn)物受體（AGE-RAGE）信號通路；低氧誘導(dǎo)因子（HIF）-1信號通路等。分子對接結(jié)果顯示白藜蘆醇與關(guān)鍵靶點對接結(jié)合能均小于0。結(jié)論 白藜蘆醇可能通過TNF、Bcl-2、CXCR4、EGFR等多個靶點，從而調(diào)節(jié)AGE-RAGE信號通路、IL-17信號通路等多條信號通路，進而抑制腫瘤細胞增殖、抑制腫瘤血管生成、促進腫瘤細胞凋亡等來發(fā)揮治療乙型病毒性肝炎相關(guān)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

武漢市知識創(chuàng)新專項項目-曙光計劃項目（2023020201020406）