基于数据挖掘和网络药理学分析中医药治疗骨折延迟愈合的用药规律和作用机制

Analysis of Medication Rules and Mechanisms of Traditional Chinese Medicine in the Treatment of Delayed Union Based on Data Mining and Network Pharmacology

摘要:

目的：运用数据挖掘、网络药理学和分子对接技术分析中医药治疗骨折延迟愈合的用药规律和作用机制。方法：通过搜集万方数据库、中国知网、维普网、中国生物医学文献数据库自建库至2025年6月30日发表的有关中医药治疗骨折延迟愈合的文献，构建数据库。采用Microsoft Excel软件对药物频次、性味归经属性进行数据录入、整理与频数统计，利用IBM SPSS Modeler 18.0平台中的Apriori算法进行关联规则分析，获取中医药治疗骨折延迟愈合的核心药物。检索TCMSP数据库并将PharmMapper数据库、中国知网文献作为数据补充来源获取核心药物活性成分及对应靶点，从GeneCards、OMIM数据库筛选骨折延迟愈合的潜在相关靶点；随后利用STRING数据库、Cytoscape3.8.0软件等进行蛋白互作（PPI） 网络分析、基因本体（GO） 功能富集分析和京都基因与基因组百科全书（KEGG） 通路富集分析；并进行分子对接验证。结果：筛选纳入方剂161首，共有中药199味，总频次为2 008次。中药药性集中于温、寒、平性，药味以甘、苦、辛味出现频率最高，归经主要归属肝、肾、脾经，功效以补虚药、活血化瘀药为主。得到核心药物组合为当归-续断-骨碎补-自然铜。核心药物组合治疗骨折延迟愈合的主要活性成分为柚皮素、豆甾-4，22-二烯–3-酮、环劳登醇酯、环阿屯酮、豆甾-4-烯-3-酮等；核心靶点为磷脂酰肌醇3-激酶α催化亚基（PIK3CA）、雌激素受体1（ESR1）、表皮生长因子受体（EGFR）、蛋白酪氨酸磷酸酶非受体型11 （PTPN11）、信号转导与转录激活因子1 （STAT1）等。KEGG 分析主要涉及信号转导子和转录激活子（JAK-STAT）、磷脂酰肌醇3-激酶-蛋白激酶B （PI3KAKT）、缺氧诱导因子-1 （HIF-1）、叉头框蛋白O （FoxO） 等信号通路。主要活性成分与核心靶点的分子对接结合能均＜-5 kcal/mol，结合稳定。结论：中医药治疗骨折延迟愈合以滋补肝肾、补血活血为法，核心药物组合“当归-续断-骨碎补-自然铜”通过柚皮素、豆甾-4，22-二烯–3-酮、环劳登醇酯、环阿屯酮、豆甾-4-烯-3-酮等成分，作用于PIK3CA、ESR1、EGFR、PTPN11、STAT1等潜在靶点，调控JAK-STAT、PI3K-AKT、HIF-1、FoxO等信号通路，促进成骨细胞分化、抑制炎症反应等过程加速骨折愈合。

Abstract:

Abstract： Objective： To analyze the medication rules and mechanisms of action of traditional Chinese medicine （TCM） in the treatment of delayed union using data mining，network pharmacology，and molecular docking techniques. Methods：Literature on TCM treatment for delayed union published from the database inception to June 30， 2025， was collected from the Wanfang Data Knowledge Service Platform （Wanfang）， China National Knowledge Infrastructure（CNKI）， China Science and Technology Journal Database （VIP）， and China Biology Medicine disc （CBM） to construct a database. Microsoft Excel was used for data entry，organization，and frequency statistics of medicinal frequencies， properties， flavors， and meridian tropisms. The Apriori algorithm in the IBM SPSS Modeler 18.0 platform was employed for association rule analysis to identify core herbal combinations for treating delayed union. Active compounds and corresponding targets of the core herbs were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）， supplemented with data from PharmMapper and CNKI literature. Potential therapeutic targets related to delayed union were screened from the Human Gene Database （GeneCards） and Online Mendelian Inheritance in Man （OMIM） databases. Protein-protein interaction （PPI） network analysis， Gene Ontology （GO） functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis were performed using the Retrieval of Interacting Genes/ Proteins （STRING） and Cytoscape 3.8.0 software. Molecular docking visualization was subsequently conducted. Results：A total of 161 prescriptions were included，involving 199 Chinese herbal medicines with a total frequency of 2 008. The herb properties were mainly warm，cold，and neutral. The most frequent flavors were sweet，bitter，and pungent. The primary meridian tropisms were the liver， kidney， and spleen meridians. The main therapeutic effects were tonifying deficiency and invigorating blood circulation and removing stasis. The core herbal combination was identified as Angelicae Sinensis Radix-Dipsaci Radix-Drynariae Rhizoma-Pyritum. The main active components of this core combination for treating delayed union were naringenin， stigmasta-4， 22-dien-3-one， cyclolaudenol ester， cycloartenone， and stigmasta-4-en-3-one. The core targets included phosphatidylinositol 3-kinase catalytic subunit alpha （PIK3CA）， estrogen receptor 1 （ESR1）， epidermal growth factor receptor （EGFR）， protein tyrosine phosphatase non-receptor type 11 （PTPN11），and signal transducer and activator of transcription 1 （STAT1）. KEGG analysis primarily involved the Janus kinase-signal transducer and activator of transcription （JAK-STAT） ， phosphatidylinositol 3-kinase/protein kinase B（ PI3K-AKT），hypoxia-inducible factor-1（ HIF-1），and forkhead box O （FoxO） signaling pathways. The binding energies of molecular docking between the main active components and core targets were all less than -5 kcal/mol，indicating stable binding affinity. Conclusion：TCM treatment for delayed union follows the principles of nourishing the liver and kidney， enriching blood， and activating blood circulation. The core herbal combination "Angelicae Sinensis Radix-Dipsaci Radix-Drynariae Rhizoma-Pyritum" acts on potential targets such as PIK3CA，ESR1，EGFR，PTPN11，and STAT1 through components including naringenin，stigmasta-4，22- dien-3-one，cyclolaudenol ester，cycloartenone，and stigmasta-4-en-3-one，thereby regulating signaling pathways such as JAK-STAT， PI3K-AKT， HIF-1， and FoxO to promote osteoblast differentiation and inhibit inflammatory responses，thus accelerating fracture healing.