桂枝茯苓丸活性成分常春藤皂苷元通过抑制JAK2/STAT3通路抑制宫颈癌细胞的生长

doi:10.12122/j.issn.1673-4254.2025.07.08

南方医科大学学报 ›› 2025, Vol. 45 ›› Issue (7): 1423-1433.doi: 10.12122/j.issn.1673-4254.2025.07.08

桂枝茯苓丸活性成分常春藤皂苷元通过抑制JAK2/STAT3通路抑制宫颈癌细胞的生长

朱胤福¹(), 李怡燃¹, 王奕¹, 黄颖而², 龚昆翔³, 郝文波¹(), 孙玲玲⁴()

^1.南方医科大学，检验与生物技术学院，广东广州 510515
^2.南方医科大学，中医药学院，广东广州 510515
^3.广州医科大学附属妇女儿童医疗中心优生围产研究所，广东广州 510623
^4.南方医科大学中西医结合医院肿瘤科，广东广州 510315

收稿日期:2025-03-13 出版日期:2025-07-20 发布日期:2025-07-17
通讯作者: 郝文波,孙玲玲 E-mail:1227643411@qq.com;haowa@126.com;sunlingling813@163.com
作者简介:朱胤福，在读硕士研究生，E-mail: 1227643411@qq.com
基金资助:
国家自然科学基金(82304781);国家自然科学基金(82404926);广东省基础与应用基础研究基金自然科学基金(2024A1515012978);广东省基础与应用基础研究基金自然科学基金(2025A1515011316)

Therapeutic mechanism of hederagenin, an active component in Guizhi Fuling Pellets, against cervical cancer in nude mice

Yinfu ZHU¹(), Yiran LI¹, Yi WANG¹, Yinger HUANG², Kunxiang GONG³, Wenbo HAO¹(), Lingling SUN⁴()

^1.School of Laboratory and Biotechnology, Southern Medical University, Guangzhou 510515, China
^2.School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
^3.Institute of Reproductive Health and Perinatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
^4.Department of Oncology, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China

Received:2025-03-13 Online:2025-07-20 Published:2025-07-17
Contact: Wenbo HAO, Lingling SUN E-mail:1227643411@qq.com;haowa@126.com;sunlingling813@163.com
Supported by:
National Natural Science Foundation of China(82304781)

摘要/Abstract

摘要：

目的基于网络药理学分析桂枝茯苓丸有效成分治疗宫颈癌的潜在作用机制，进一步通过实验手段对其抗肿瘤作用进行验证。方法利用TCMSP、Genecards、OMIM、TTD、Swiss Target Prediction等数据库，获得桂枝茯苓丸的作用靶点和宫颈癌发病相关的靶点。构建靶点蛋白质相互作用网络，进行GO生物学过程与KEGG通路富集分析，使用Cytoscape v10.0.0构建桂枝茯苓丸治疗宫颈癌的“中药-有效成分-靶点-通路”网络。利用CB-Dock2软件对药物和潜在作用靶点进行分子对接，预测桂枝茯苓丸有效成分的具体作用靶点。在实验验证部分，采用CCK-8、Western blotting实验体外验证桂枝茯苓丸有效成分的抗肿瘤活性。动物实验中，使用12只雌性BALB/c裸鼠构建裸鼠皮下种植瘤模型并将其分为2组（DMSO组及用药组，6只/组），用于评估药物体内抗肿瘤活性，并行组织切片苏木精-伊红与免疫组织化学染色进一步评估药物体内使用安全性与有效性。结果分析显示，桂枝茯苓丸共有338个活性成分，涉及247个作用靶点。宫颈癌发病相关的靶点共10127个，通过取交集获得桂枝茯苓丸有效成分治疗宫颈癌的潜在作用靶点195个。基于节点度分析筛选出关键靶点为GABRA1、PTK2、JAK2、HTR3A、GSR和IL-17，并将它们与桂枝茯苓丸的关键前10名活性成分进行后续的分子对接。分子对接结果显示常春藤皂苷元，菜油甾醇，豆甾醇等成分与关键靶点具有较低的结合能。基因本体富集分析显示，桂枝茯苓丸有效成分在治疗宫颈癌主要集中在对类固醇激素，氧化应激，脂多糖等生物学过程。常春藤皂苷元在体外和体内都能够表现出抗肿瘤活性，细胞生长受到抑制（P<0.05），同时STAT3磷酸化水平降低（P<0.05）。动物实验提示，裸鼠皮下瘤体积生长速度更慢（P<0.05），且常春藤皂苷元的体内使用具有一定的安全性。结论桂枝茯苓丸中的多种有效活性成分可通过多个途径抑制宫颈癌细胞的生长，从而发挥抗肿瘤作用。其中，常春藤皂苷元可能通过与JAK2蛋白紧密结合，抑制STAT3磷酸化，进而显著发挥其抗肿瘤活性。

关键词: 网络药理学, 桂枝茯苓丸, 宫颈癌, 人乳头瘤病毒感染, 常春藤皂苷元

Abstract:

Objective To explore the therapeutic mechanism of Guizhi Fuling (GZFL) Pellets against cervical cancer. Methods Publicly available databases were used to identify the targets of GZFL Pellets and cervical cancer to construct the protein-protein interaction (PPI) network, followed by GO biological process and KEGG pathway enrichment analysis of the hub genes. The "Traditional Chinese Medicine-Active Ingredients-Targets-Pathways" network for GZFL Pellets in cervical cancer treatment was generated using Cytoscape v10.0.0, and molecular docking of the drug and potential targets was performed to predict the specific targets of active components in Guizhi Fuling Pellets. The inhibitory effects of hederagenin, an active ingredient in GZFL Pellets, was tested in cultured cervical cancer cells and in nude mice bearing cervical cancer xenografts. Results GZFL Pellets contain 338 active components targeting 247 action sites. A total of 10127 cervical cancer-related targets were obtained, and among them 195 were identified as potential therapeutic targets of GZFL Pellets for cervical cancer treatment, including the key targets of GABRA1, PTK2, JAK2, HTR3A, GSR, and IL-17. Molecular docking study showed low binding energies of the active components such as hederagenin, campesterol, and stigmasterol for protein-molecule interaction. GO enrichment analysis suggested that GZFL Pellets inhibited cervical cancer primarily by regulating responses to steroid hormones, oxidative stress, and lipopolysaccharides. Among the active components of GZFL Pellets, hederagenin was found to inhibit cervical cancer cells in vitro and significantly reduced STAT3 phosphorylation level in the cancer cells. In nude mice bearing cervical cancer xenografts, hederagenin effectively inhibited tumor growth rate without causing obvious adverse effects. Conclusion GZFL Pellets inhibit cervical cancer cell growth through its multiple active components that target different pathways. Among these components, hederagenin inhibits tumor cell growth possibly by directly binding to JAK2 protein to inhibit STAT3 phosphorylation.

Key words: network pharmacology, Guizhi Fuling Pellets, cervical cancer, HPV infection, hederagenin

朱胤福, 李怡燃, 王奕, 黄颖而, 龚昆翔, 郝文波, 孙玲玲. 桂枝茯苓丸活性成分常春藤皂苷元通过抑制JAK2/STAT3通路抑制宫颈癌细胞的生长[J]. 南方医科大学学报, 2025, 45(7): 1423-1433.

Yinfu ZHU, Yiran LI, Yi WANG, Yinger HUANG, Kunxiang GONG, Wenbo HAO, Lingling SUN. Therapeutic mechanism of hederagenin, an active component in Guizhi Fuling Pellets, against cervical cancer in nude mice[J]. Journal of Southern Medical University, 2025, 45(7): 1423-1433.

图/表 9

图1 "中药-活性成分-靶点"网络的构建

Fig.1 Construction of the "Traditional Chinese Medicine-Active Ingredients-Targets" Network. A:Venn diagram of the drug targets and cervical cancer targets. B: Traditional Chinese medicine-active ingredient-target network of Guizhi Fuling Pellets against cervical cancer.

表1 网络中草药和化合物的拓扑参数

Tab.1 Topology parameters of the herbs and compounds in the network

Name	Betweenness centrality	Closeness centrality	Degree	Eccentricity	Neighborhood connectivity	Number of undirected edges	Type
Quercetin	0.12874832	0.465960666	44	4	32.38636364	44	ingredient
Beta-sitosterol	0.042529052	0.447024673	26	4	60.03846154	26	ingredient
Kaempferol	0.054556646	0.450951684	31	4	50.90322581	31	ingredient
(+)-Catechin	0.01968019	0.426002766	15	5	94.73333333	15	ingredient
Hederagenin	0.108300219	0.443165468	17	5	59.58823529	17	ingredient
Stigmasterol	0.011819554	0.421340629	16	5	62.625	16	ingredient
Sitosterol	0.011819554	0.421340629	16	5	62.625	16	ingredient
Luteolin	0.041269784	0.42837274	22	4	51.40909091	22	ingredient
Baicalein	0.022662695	0.422496571	18	4	76.83333333	18	ingredient
Campesterol	0.003171002	0.417910448	10	5	112.4	10	ingredient

图2 交集靶点的GO和KEGG富集分析

Fig.2 GO and KEGG enrichment analysis of the intersection targets. A: PPI network constructed and visualized using Cytoscape v10.0.0. Nodes are colored based on the degrees. The degree values range from large to small, following a continuous mapping from yellow to pink. B: Top 10 items for the biological process (BP), cellular component (CC), and molecular function (MF) enrichment analysis in the GO enrichment analysis. The orange section represents the biological processes. The green part represents the cellular component. The blue part represents the molecular function. C: Top 10 items of the KEGG pathway enrichment analysis.

图3 靶蛋白和活性分子对接结果

Fig.3 Molecular docking results of the target proteins and the active molecules. A: Heatmap of the molecular docking fraction showing the binding energy of target proteins and active compounds (kcal/mol). B: Molecular docking model for JAK 2 and hederagenin. C: Molecular docking model for GSR and campesterol. D: Molecular docking model for HTR 3 A and beta-sitosterol.

表2 预测的活性成分与靶点的结合能

Tab.2 Binding energy between the predicted active components and targets

Sample	GABRA1	PTK2	JAK2	HTR3A	GSR	IL-17
(+)-catechin	-8.1	-6.7	-8.7	-8.6	-8.7	-9.5
Baicalein	-8.1	-6.9	-9.4	-8.8	-8.7	-9.2
Beta-sitosterol	-4.3	-8.2	-9.6	-10.8	-10.7	-10.4
Campesterol	-4.6	-8	-9.4	-11.3	-10.5	-9.2
Hederagenin	-8.6	-6.9	-10.7	-9.4	-11.1	-10.2
Kaempferol	-7.7	-7	-8.8	-8.5	-8.9	-8.8
Luteolin	-8.5	-8.5	-9	-9	-9	-9.1
Sitosterol	-4.3	-7.6	-9.4	-10.2	-10.8	-9.4
Quercetin	-8.1	-8.9	-9.6	-9.2	-9.1	-8.8
Stigmasterol	-4.7	-8.6	-10.0	-10.8	-11	-9.3
Isocorypalmine	-8.0	-8.2	-8.2	-8.9	-9.7	-8.7

表3 药物-靶点结合的活性口袋氨基酸

Tab. 3 Active curpockets of the amino acids

	JAK2-hederagenin	GSR-campesterol	HTR3A-beta-sitosterol
Chain A	LYS607 HIS608 GLU652 LYS655 GLN656 TRP659 HIS662 GLU666 PRO692 PHE694 PHE798 ARG799 ALA800 ILE802 ARG803 ASN806	LYS67 TRP70 ASN71 VAL74 PHE78 PRO376 PRO405 MET406 TYR407 LEU438 GLY439 ASP441 GLU442 PRO468 SER470	PHE244 VAL247 SER248 LEU249 LEU251 PRO252 PHE255 LEU256 THR279 LEU280 LEU282 GLY283 TYR284 VAL286 PHE287 ILE290 VAL291 ASP293 THR294
Chain B	ASP768 ARG769 HIS770 GLN771 LEU772 ASP789 TYR790 GLU791 HIS794		LEU281 SER285 LEU288 VAL291 SER292 LEU295 PRO296 ALA297 THR298 ALA299 GLY301 THR302 PRO303 GLY306 VAL307 PHE309 VAL310 MET313 ALA314 VAL317

图4 常春藤皂苷元在体外抑制宫颈癌细胞的生长

Fig. 4 Hederagenin inhibits growth of cervical cancer cells in vitro. A: IC50 curve of hederagenin against U14 cells. B, C: Viability of U14 cells treated with high-concentration (B) and low-concentration (C) hederagenin. D, E: Western blotting and quantitative analysis of STAT3 phosphorylation inhibited by hederagenin treatment for 72 h. *P<0.05, ***P<0.001.

图5 常春藤皂苷元在体内抑制宫颈癌细胞的生长

Fig.5 Hederagenin inhibits growth of cervical cancer xenografts in nude mice. A: Gross observation of the dissected tumors. B: Tumor growth curve during hederagenin treatment. C: HE staining and Ki-67 immunohistochemistry of the tumor sections. D: Weight of the tumors. E: Body weight curve of the nude mice during hederagenin treatment. *P<0.05.

图6 取材肝、脾、肾切片的HE染色结果

Fig. 6 HE staining results of the liver, spleen and kidney sections from the tumor-bearing mice.

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桂枝茯苓丸活性成分常春藤皂苷元通过抑制JAK2/STAT3通路抑制宫颈癌细胞的生长

Therapeutic mechanism of hederagenin, an active component in Guizhi Fuling Pellets, against cervical cancer in nude mice

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