通讯作者: 翟婷婷, Ztt1995wym@163.com

DOI：10.12201/bmr.202606.00065

Mechanism of Medroxyprogesterone Acetate Against Endometrial Cancer Based on Network Toxicology and Molecular Docking

• 摘要：摘要目的：基于网络毒理学与分子对接方法，系统预测甲羟孕酮作用于子宫内膜癌的潜在靶点，探讨其多靶点、多通路的分子机制。方法：利用CTD、STITCH、SwissTargetPrediction数据库获取MPA相关靶点；从GeneCards、OMIM、TTD数据库获取EC疾病靶点；利用Cytoscape软件构建MPA-靶点-EC网络及蛋白质互作（PPI）网络，并通过拓扑分析筛选核心靶点。再对核心靶点进行GO功能与KEGG通路富集分析。最后，对筛选出的前五位核心靶点进行分子对接验证。结果：共获得甲羟孕酮靶点410个，子宫内膜癌相关基因2312个，交集靶点165个。核心靶点主要包括TP53、FN1、TNF、ESR1、FOXO1等。 GO富集分析表明，核心靶点主要富集于活性氧代谢过程、腺体发育、凋亡信号通路调控、缺氧应答、平滑肌增殖的调控、雌激素反应元件结合等生物过程。KEGG通路富集于PI3K-Akt、FoxO、p53、HIF-1、HPV及类固醇激素生物合成等信号通路。分子对接验证显示MPA与TP53、FN1、ESR1等核心靶点具有强结合亲和力（结合自由能ΔG < -8.0 kcal/mol）。结论：甲羟孕酮可能通过调控TP53、FN1、TNF、ESR1、FOXO1等多靶点，干预PI3K-Akt、FoxO、p53、HIF-1、HPV及类固醇激素生物合成等多条信号通路，影响肿瘤抑制、细胞增殖、凋亡、缺氧应激、炎症反应、激素调节及重构肿瘤微环境激素反应，从而发挥抗EC作用。然而，其较高的预测毒性风险提示临床应用需谨慎。本研究结果为MPA治疗EC提供了新的多靶点作用机制假说。

  关键词： 甲羟孕酮；子宫内膜癌；网络毒理学；分子对接；作用机制; ; ; ; 

   

  Abstract: AbstractObjective: To systematically predict the potential targets of medroxyprogesterone acetate (MPA) against endometrial cancer (EC) and explore its multi-target, multi-pathway molecular mechanism based on network toxicology and molecular docking.Methods: MPA-related targets were obtained from the CTD, STITCH, and SwissTargetPrediction databases; EC-related disease targets were retrieved from GeneCards, OMIM, and TTD databases. Cytoscape software was used to construct an MPA-target-EC network and a protein–protein interaction (PPI) network, and core targets were screened via topological analysis. Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the core targets. Finally, molecular docking verification was conducted for the top five core targets.Results: A total of 410 MPA-related targets, 2312 EC-related genes, and 165 overlapping targets were identified. The core targets mainly included TP53, FN1, TNF, ESR1, and FOXO1. GO enrichment analysis showed that the core targets were mainly enriched in biological processes such as reactive oxygen species metabolic process, gland development, regulation of apoptotic signaling pathway, response to hypoxia, regulation of smooth muscle cell proliferation, and estrogen response element binding. KEGG pathway enrichment was observed in the PI3K-Akt, FoxO, p53, HIF-1, HPV, and steroid hormone biosynthesis signaling pathways. Molecular docking verification demonstrated that MPA exhibited strong binding affinity with core targets including TP53, FN1, and ESR1 (binding free energy ΔG < ?8.0 kcal/mol).Conclusion: Medroxyprogesterone acetate (MPA) may exert anti-endometrial cancer (EC) effects by regulating multiple targets such as TP53, FN1, TNF, ESR1, and FOXO1, interfering with multiple signaling pathways including PI3K-Akt, FoxO, p53, HIF-1, HPV, and steroid hormone biosynthesis, and affecting tumor suppression, cell proliferation, apoptosis, hypoxic stress, inflammatory response, hormone regulation, and hormone response in tumor microenvironment remodeling. However, its high predicted toxicity risk suggests that caution is required in clinical application. The results of this study provide a new hypothesis for the multi-target mechanism of MPA in the treatment of EC.

  Key words: medroxyprogesterone acetate; endometrial cancer; network toxicology; molecular docking; mechanism of action

  提交时间：2026-06-21

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• 序号	提交日期	编号	操作
  1	2026-04-17	10.12201/bmr.202606.00065V1	下载

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