目的 利用網(wǎng)絡(luò)藥理學(xué)及分子對(duì)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(jī)制。方法 運(yùn)用Swiss Target Prediction和Target Net數(shù)據(jù)庫(kù)預(yù)測(cè)白藜蘆醇的潛在作用靶點(diǎn)；檢索GeneCards、OMIM、DisGeNET數(shù)據(jù)庫(kù)獲取乙型病毒性肝炎相關(guān)性肝癌的靶點(diǎn)信息；通過(guò)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(diǎn)。運(yùn)用STRING數(shù)據(jù)庫(kù)構(gòu)建交集靶點(diǎn)的PPI網(wǎng)絡(luò)；使用Cytoscape軟件進(jìn)行網(wǎng)絡(luò)拓?fù)浞治龊Y選關(guān)鍵靶點(diǎn)；利用Metascape數(shù)據(jù)庫(kù)對(duì)交集靶點(diǎn)進(jìn)行基因本體（GO）和京都基因組百科全書(shū)（KEGG）通路分析；通過(guò)Cytoscape建立“藥物–靶點(diǎn)–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(jī)制。最后通過(guò)分子對(duì)接明確白藜蘆醇與關(guān)鍵靶點(diǎn)的作用機(jī)制。結(jié)果 預(yù)測(cè)得到白藜蘆醇靶點(diǎn)496個(gè)，篩選、去重得到疾病靶點(diǎn)1 018個(gè)，最后得到交集靶點(diǎn)48個(gè)。排名前10位的關(guān)鍵靶點(diǎn)分別為腫瘤壞死因子（TNF）、基質(zhì)金屬蛋白酶9（MMP9）、表皮生長(zhǎng)因子受體（EGFR）、B淋巴細(xì)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(guò)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(guò)程、細(xì)胞遷移等功能，參與的信號(hào)傳導(dǎo)通路主要包括癌癥中的通路、脂質(zhì)與動(dòng)脈粥樣硬化、趨化因子信號(hào)通路、白細(xì)胞介素（IL）-17信號(hào)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(hào)通路；低氧誘導(dǎo)因子（HIF）-1信號(hào)通路等。分子對(duì)接結(jié)果顯示白藜蘆醇與關(guān)鍵靶點(diǎn)對(duì)接結(jié)合能均小于0。結(jié)論 白藜蘆醇可能通過(guò)TNF、Bcl-2、CXCR4、EGFR等多個(gè)靶點(diǎn)，從而調(diào)節(jié)AGE-RAGE信號(hào)通路、IL-17信號(hào)通路等多條信號(hào)通路，進(jìn)而抑制腫瘤細(xì)胞增殖、抑制腫瘤血管生成、促進(jìn)腫瘤細(xì)胞凋亡等來(lái)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(shí)創(chuàng)新專項(xiàng)項(xiàng)目-曙光計(jì)劃項(xiàng)目（2023020201020406）