Target prediction and preliminary validation of quercetin in treatment of endometriosis

ZHANG Yi; WU Lulu; TANG Li; CUI Jiao; YUAN Wanjing; GONG Wenying; ZHU Jiao; LYU Xiuwei

doi:10.16016/j.2097-0927.202504113

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Target prediction and preliminary validation of quercetin in treatment of endometriosis

Basic Medicine | 更新时间：2025-08-25

- Target prediction and preliminary validation of quercetin in treatment of endometriosis
- Journal of Army Medical University Vol. 47, Issue 16, Pages: 1913-1922(2025)
- 作者机构：
  
  1.湖南中医药大学第二附属医院，湖南长沙
  2.华中科技大学同济医学院附属武汉中心医院，湖北武汉
  3.火箭军特色医学中心，北京
- 作者简介：
  
  LYU Xiuwei， E-mail： lxwhelen@126.com
- 基金信息：
  
  the Project of Medical Scientific Research of Hunan Provincial Health Commission(D202305017387);the Key Project of Scientific Research for Traditional Chinese Medicine of Hunan Province(A2024039);the Natural Science Foundation of Hunan Province(2024JJ9444);the Construction Project of National Famous Traditional Chinese Medicine Expert Inheritance Studio in 2022(国中医药人教函〔2022〕75号)
- DOI：10.16016/j.2097-0927.202504113
  CLC： R285.5;R341;R711.71
- Received：27 April 2025，
  
  Revised：19 May 2025，
  
  Published：30 August 2025
- 稿件说明：
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张翼，吴璐璐，唐俐，等.槲皮素治疗子宫内膜异位症的靶点预测及初步鉴定［J］.陆军军医大学学报，2025，47（16）：1913-1922.DOI：10.16016/j.2097-0927.202504113.

ZHANG Y，WU L L，TANG L，et al.Target prediction and preliminary validation of quercetin in treatment of endometriosis［J］.J Army Med Univ，2025，47（16）：1913-1922.DOI：10.16016/j.2097-0927.202504113.
张翼，吴璐璐，唐俐，等.槲皮素治疗子宫内膜异位症的靶点预测及初步鉴定［J］.陆军军医大学学报，2025，47（16）：1913-1922.DOI：10.16016/j.2097-0927.202504113. DOI：

ZHANG Y，WU L L，TANG L，et al.Target prediction and preliminary validation of quercetin in treatment of endometriosis［J］.J Army Med Univ，2025，47（16）：1913-1922.DOI：10.16016/j.2097-0927.202504113. DOI：

摘要

目的

基于网络药理学整合分析探讨槲皮素治疗子宫内膜异位症（endometriosis，EMT）的多靶点作用机制。

方法

通过TCMSP数据库收集槲皮素活性靶点，GEO数据库筛选EMT差异基因，比对获得槲皮素治疗EMT的潜在作用靶点；采用功能富集分析探讨靶点的生物学功能，构建蛋白质互作网络识别核心靶点。通过分子对接及分子动力学模拟验证槲皮素-靶蛋白结合特性。选择结合能最小的前两对靶蛋白（HSP90AB1、AR）进行细胞实验验证：采用人源EMT永生化异位内膜上皮细胞系12Z（

=6），通过CCK-8法测定槲皮素对12Z细胞活力的影响，计算48 h的半数抑制浓度（half inhibitory concentration，IC50）；设置槲皮素浓度梯度（0、30、60、90 μmol/L），通过划痕实验、细胞侵袭实验评估迁移、侵袭能力；Western blot检测HSP90AB1、AR蛋白表达变化。

结果

筛选获得49个槲皮素治疗EMT的潜在靶点及10个核心靶点。功能富集显示，靶点显著富集于AGE-RAGE、ErbB及TNF等炎症相关信号通路，Th17细胞分化、T细胞受体及B细胞受体等免疫相关信号通路，VEGF等血管生成相关通路，雌激素及GnRH等激素调控通路。分子对接表明，槲皮素与所有核心靶蛋白之间均呈现良好的结合活性（

-5 kcal/mol），其中AR、EGFR、FOS、ERBB2、HSP90AB1的结合能尤为显著（

-7 kcal/mol）。分子动力学模拟显示，槲皮素与AR、HSP90AB1之间形成持续的氢键相互作用，可形成稳定的复合物。CCK-8实验、划痕实验、细胞侵袭实验提示槲皮素呈浓度依赖性地抑制12Z细胞的-活力及迁移、侵袭能力，其中60、90 μmol/L槲皮素抑制效果更佳（

0.001）；Western blot实验显示不同浓度槲皮素处理12Z细胞48 h，HSP90AB1蛋白及AR蛋白表达升高，其中90 μmol/L槲皮素最为明显（HSP90AB1蛋白：

0.05；AR蛋白：

0.001），且HSP90AB1/AR表达水平恢复与异位内膜细胞的活力及迁移、侵袭能力呈正相关。

结论

槲皮素可通过多靶点、多途径治疗子宫内膜异位症，其中稳定HSP90AB1/AR复合物并增强其蛋白表达是重要机制之一。

Abstract

Objective‍　‍To investigate the multi-target mechanisms of quercetin in treating endometriosis (EMT) through integrative network pharmacology analysis. Methods‍　‍Active targets of quercetin were collected from the TCMSP database

while EMT-related differentially expressed genes (DEGs) were identified through the Gene Expression Omnibus (GEO) dataset. A comparative analysis was conducted to pinpoint potential therapeutic targets of quercetin for EMT treatment. Functional enrichment analyses were employed to investigate the biological functions associated with these targets

and a protein-protein interaction (PPI) network was conducted to identify core targets. Molecula

r docking and dynamics simulations were performed to validate the binding characteristics between quercetin and the core targets. The top 2 target protein pairs

HSP90AB1 and AR

exhibiting the lowest binding energy

were selected for subsequent cellular experimental validation. Human EMT-immortalized ectopic endometrial epithelial cell line 12Z (

independent replicates) was subjected

and CCK-8 assay was used to determine ehe effects of quercetin on cell viability and proliferation

and the half-maximal inhibitory concentration (IC50) was calculated at 48 h after treatment. Then the 12Z cells were treated with quercetin at a concentration gradient of 0

60 and 90 μmol/L

the migration and invasion abilities were assessed with cell scratch and cell invasion assays. Western blotting was conducted to detect the changes in the expression of HSP90AB1 and AR proteins after different doses of treatment. Results‍　‍There were 49 potential EMT-related therapeutic targets and 10 core targets identified. Functional enrichment analyses revealed that these targets were significant enriched in inflammation-related signaling pathways

including AGE-RAGE

ErbB and TNF; immune-related pathways

such as Th17 cell differentiation

T/B cell receptor signaling; angiogenesis-related pathways like VEGF; and hormonal regulatory pathways involving estrogen and GnRH. Molecular docking demonstrated that quercetin exhibited favorable binding activity (binding energy

-5 kcal/mol) with all core target proteins

with particularly strong binding energies (

-7 kcal/mol) observed for AR

EGFR

FOS

ERBB2

and HSP90AB1. Molecular dynamics simulations revealed that quercetin forms sustained hydrogen bond interactions with AR and HSP90AB1

facilitating the formation of stable complexes. CCK-8 assay

cell scratch assay

and transwell invasion assay indicated that quercetin inhibited the proliferative activity

and migrative and invasive abilities of 12Z cells in a concentration-dependent manner

with more pronounced in

hibitory effects observed at 60 and 90 μmol/L quercetin (

0.001); Western blotting revealed that treatment of 12Z cells with varying quercetin concentrations for 48 h up-regulated the expression of HSP90AB1 and AR

with the most significant increase observed at 90 μmol/L quercetin (HSP90AB1

0.05; AR

0.001). The restored expression levels of HSP90AB1 and AR showed positive correlations with the proliferative activity

migrative and invasive abilities of ectopic endometrial cells. Conclusion‍　‍Quercetin effectively addresses endometriosis through multiple molecular targets and signaling pathways

and stabilization of the HSP90AB1/AR complex and subsequent protein upregulation represents a key therapeutic mechanism.

关键词

Keywords

references

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