目的 運(yùn)用網(wǎng)絡(luò)藥理學(xué)技術(shù)探究知柏地黃丸治療乳腺癌內(nèi)分泌耐藥的活性成分、潛在靶點(diǎn)和作用機(jī)制。方法 通過TCMSP數(shù)據(jù)庫、TCM-ID數(shù)據(jù)庫和BATMAN-TCM數(shù)據(jù)庫，篩選知柏地黃丸的有效活性成分和作用靶點(diǎn)，利用GeneCards數(shù)據(jù)庫、OMIM數(shù)據(jù)庫、TTD數(shù)據(jù)庫和GEO數(shù)據(jù)庫檢索獲得乳腺癌內(nèi)分泌治療耐藥的相關(guān)靶基因，并與活性成分作用靶點(diǎn)取交集得到共同靶點(diǎn)；通過String 11.5數(shù)據(jù)庫構(gòu)建知柏地黃丸治療乳腺癌內(nèi)分泌耐藥的蛋白質(zhì)互作（PPI）網(wǎng)絡(luò)，并借助Cytoscape 3.8.2軟件的CytoNCA插件篩選核心靶點(diǎn)；通過Metascape基因功能注釋分析工具對(duì)交集靶點(diǎn)進(jìn)行基因本體（GO）和京都基因組百科全書（KEGG）通路富集分析，使用Cytoscape 3.8.2軟件構(gòu)建藥物活性成分–靶點(diǎn)–通路相互作用網(wǎng)絡(luò)，獲取核心活性成分。結(jié)果 共篩選出知柏地黃丸活性成分80個(gè)，與疾病的交集靶點(diǎn)117個(gè)，主要涉及腫瘤蛋白p53（TP53）、蛋白激酶B1（Akt1）、腫瘤壞死因子（TNF）、白細(xì)胞介素-6（IL6）、雌激素受體1（ESR1）、絲裂原活化蛋白激酶1（MAPK1）等。KEGG通路富集分析顯示磷脂酰肌醇3-激酶（PI3K）/Akt、MAPK、核因子-κB（NF-κB）、雌激素等信號(hào)通路可能是知柏地黃丸治療乳腺癌內(nèi)分泌耐藥的關(guān)鍵信號(hào)通路，由藥物活性成分–靶點(diǎn)–通路網(wǎng)絡(luò)得出槲皮素、山柰酚、脫水淫羊藿素、β-谷甾醇、薯蕷皂苷元等是發(fā)揮作用的核心活性成分。結(jié)論 知柏地黃丸中的槲皮素、山柰酚、脫水淫羊藿素、β-谷甾醇、薯蕷皂苷元等核心活性成分，能夠作用于TP53、Akt1、TNF、IL-6、ESR1、MAPK1等多個(gè)關(guān)鍵靶點(diǎn)，調(diào)節(jié)PI3K-Akt、MAPK、NF-κB、雌激素等信號(hào)通路，發(fā)揮治療乳腺癌內(nèi)分泌耐藥的作用。

Objective To explore the active ingredients, potential targets and mechanism of action of Zhibai Dihuang Pills in treatment of endocrine drug resistance in breast cancer by network pharmacology. Methods Through TCMSP database, TCM-ID database and BATMAN-TCM database, the active ingredients and targets of Zhibai Dihuang Pills was screened. And the targets related to drug resistance of breast cancer endocrine therapy were retrieved by GeneCards database, OMIM database, TTD database and GEO database. The intersection of component targets and disease targets was used to obtain common targets. The protein-protein interaction network of Zhibai Dihuang Pills for the treatment of endocrine resistance of breast cancer was constructed by String 11.5 database, and the core targets were screened by CytoNCA plug-in of Cytoscape 3.8.2 software. The GO and KEGG pathway enrichment analysis of intersection targets was performed by Metascape gene function annotation analysis tool. The interaction network of active ingredient-target-pathway was constructed by Cytoscape 3.8.2 software to obtain the core active ingredients. Results A total of 80 active components of Zhibai Dihuang Pills were screened, and 117 intersecting targets with diseases were screened, mainly involving TP53, Akt1, TNF, IL-6, ESR1, MAPK1 and so on. KEGG pathway enrichment analysis showed that PI3K/Akt, MAPK, NF-κB and estrogen may be the key signal pathways of Zhibai Dihuang Pills in the treatment of breast cancer endocrine resistance. Quercetin, kaempferol, dehydrated icariin, β-sitosterol and diosgenin are the core active components from the drug active component- target-pathway network. Conclusion Core active ingredients such as quercetin, kaempferol, Anhydroicaritin, β-sitosterol and diosgenin in Zhibai Dihuang Pills may affect the signaling pathways of PI3K/Akt, MAPK, NF-κB and estrogen by acting on multiple targets such as TP53, Akt1, TNF, IL-6, ESR1 and MAPK1, which plays a role in the treatment of breast cancer endocrine resistance.

R979.1

山東省中醫(yī)藥科技項(xiàng)目（2021M091）；齊魯中醫(yī)藥優(yōu)勢(shì)?？萍航ㄔO(shè)項(xiàng)目（腫瘤科）（魯衛(wèi)函[2022]46號(hào)）