目的 基于網(wǎng)絡(luò)藥理學(xué)、分子對(duì)接以及體外實(shí)驗(yàn)探究槲皮素增敏阿霉素治療乳腺癌的作用機(jī)制。方法 通過TCMSP、GeneCards、OMIM等數(shù)據(jù)庫及Venny 2.1獲得槲皮素增敏乳腺癌治療的潛在靶點(diǎn)，將共同靶點(diǎn)輸入STRING數(shù)據(jù)庫獲取靶標(biāo)蛋白相互作用（PPI）網(wǎng)絡(luò)關(guān)系，并利用R軟件進(jìn)行基因本體（GO）功能富集分析，京都基因和基因百科全書（KEGG）篩選作用通路靶點(diǎn)，再采用Auto dock軟件進(jìn)行分子對(duì)接模擬，最后通過細(xì)胞毒性、平板克隆實(shí)驗(yàn)以及Western blotting驗(yàn)證槲皮素增敏阿霉素抗乳腺癌效應(yīng)及作用機(jī)制。結(jié)果 網(wǎng)絡(luò)藥理學(xué)分析發(fā)現(xiàn)，槲皮素與乳腺癌交叉作用靶點(diǎn)有155個(gè)，其中核心靶點(diǎn)主要包括腫瘤蛋白p53（p53）、蛋白激酶B1（Akt1）、轉(zhuǎn)錄因子AP-1（JUN）、原癌基因（MYC）、成纖維細(xì)胞生長(zhǎng)因子受體（FGFR）、信號(hào)轉(zhuǎn)錄與激活因子3（STAT3）等；分子對(duì)接模擬現(xiàn)實(shí)槲皮素與Akt1和p53有良好的親和性。細(xì)胞實(shí)驗(yàn)表明，槲皮素在較高濃度時(shí)可以抑制細(xì)胞增殖和誘導(dǎo)細(xì)胞凋亡；增敏阿霉素的細(xì)胞毒性，有效提升阿霉素對(duì)4T1及其耐藥細(xì)胞的殺傷效應(yīng)。Western blotting檢測(cè)表明，槲皮素作用后細(xì)胞中Akt1蛋白表達(dá)呈下降趨勢(shì)，而P53蛋白則被明顯上調(diào)（P＜0.001）。結(jié)論 槲皮素可以阿霉素抗乳腺癌細(xì)胞增殖并誘導(dǎo)細(xì)胞凋亡，其潛在機(jī)制主要是調(diào)節(jié)p53、Akt1信號(hào)通路，降低乳腺癌治療抵抗性，提升治療效應(yīng)。

Objective To investigate the mechanisms of quercetin in enhancing the sensitivity of adriamycin for breast cancer treatment using the network pharmacology, molecular docking, and in vitro studies. Methods Targets of quercetin sensitization in breast cancer treatment were identified by utilizing the TCMSP, GeneCards, OMIM databases and Venny 2.1. The common targets were then input into the STRING database to construct a PPI network, and GO functional enrichment analysis was performed using R software, KEGG screening for action pathway targets. Molecular docking were conducted using AutoDock software. Finally, the anti-breast cancer effects and mechanisms of quercetin sensitizing adriamycin were validated through cytotoxicity assays, plate cloning assays, and Western blotting. Results Network pharmacology analysis revealed 155 overlapping targets between quercetin and breast cancer, with key targets including p53, Akt1, JUN, P53, MYC, FGFR, STAT3, etc. Quercetin has good affinity with Akt1 and p53 in the simulation of molecular docking. In vitro cellular experiments confirmed that quercetin can inhibit cell proliferation and induce apoptosis at higher concentrations, and significantly enhancing adriamycin impact on both 4T1 cells and their drug-resistant cells. Western blotting analysis revealed a significant decrease in Akt1 protein expression, and increase p53 protein expression in 4T1 cells treated with quercetin (P < 0.001). Conclusion Quercetin can inhibit the proliferation and induce apoptosis of breast cancer cells by adriamycin, and its potential mechanism is mainly to regulate p53 and Akt1 signaling pathways, reduce the resistance to breast cancer treatment, and enhance the therapeutic effect.

R287.4

國(guó)家自然科學(xué)基金資助項(xiàng)目（32301126）；安徽省高校優(yōu)秀青年科研項(xiàng)目（2024AH030039）；安徽省新型研發(fā)機(jī)構(gòu)安慶市林業(yè)科技創(chuàng)新研究院開放基金項(xiàng)目（Ly202401）；安徽省博士后科研項(xiàng)目（2024C857）