目的 基于网络药理学、分子对接以及体外实验探究槲皮素增敏阿霉素治疗乳腺癌的作用机制。方法 通过TCMSP、GeneCards、OMIM等数据库及Venny 2.1获得槲皮素增敏乳腺癌治疗的潜在靶点，将共同靶点输入STRING数据库获取靶标蛋白相互作用（PPI）网络关系，并利用R软件进行基因本体（GO）功能富集分析，京都基因和基因百科全书（KEGG）筛选作用通路靶点，再采用Auto dock软件进行分子对接模拟，最后通过细胞毒性、平板克隆实验以及Western blotting验证槲皮素增敏阿霉素抗乳腺癌效应及作用机制。结果 网络药理学分析发现，槲皮素与乳腺癌交叉作用靶点有155个，其中核心靶点主要包括肿瘤蛋白p53（p53）、蛋白激酶B1（Akt1）、转录因子AP-1（JUN）、原癌基因（MYC）、成纤维细胞生长因子受体（FGFR）、信号转录与激活因子3（STAT3）等；分子对接模拟现实槲皮素与Akt1和p53有良好的亲和性。细胞实验表明，槲皮素在较高浓度时可以抑制细胞增殖和诱导细胞凋亡；增敏阿霉素的细胞毒性，有效提升阿霉素对4T1及其耐药细胞的杀伤效应。Western blotting检测表明，槲皮素作用后细胞中Akt1蛋白表达呈下降趋势，而P53蛋白则被明显上调（P＜0.001）。结论 槲皮素可以阿霉素抗乳腺癌细胞增殖并诱导细胞凋亡，其潜在机制主要是调节p53、Akt1信号通路，降低乳腺癌治疗抵抗性，提升治疗效应。

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

国家自然科学基金资助项目（32301126）；安徽省高校优秀青年科研项目（2024AH030039）；安徽省新型研发机构安庆市林业科技创新研究院开放基金项目（Ly202401）；安徽省博士后科研项目（2024C857）