中国药物警戒 ›› 2025, Vol. 22 ›› Issue (11): 1211-1216.
DOI: 10.19803/j.1672-8629.20250575

• 中西药联用的风险调控与预警研究专栏 • 上一篇    下一篇

基于ceRNA网络与分子对接的别嘌醇肾脏损伤标志物预测研究

高福君1, 张晓朦1,2, 陈莉娟1, 蔡海丽1, 刘鑫龙1, 朱春胜3, 张冰1,2*   

  1. 1北京中医药大学中药学院,北京 100029;
    2北京中医药大学中药药物警戒与合理用药研究中心,北京 100029;
    3郑州大学第一附属医院中药科,河南 郑州 450000
  • 收稿日期:2025-08-17 出版日期:2025-11-15 发布日期:2025-11-14
  • 通讯作者: *张冰,女,博士,主任医师,教授·博导,中药防治代谢性疾病、中药药物警戒与合理用药。E-mail:zhangb@bucm.edu.cn
  • 作者简介:高福君,女,硕士,中药防治代谢性疾病、中药药物警戒与合理用药。
  • 基金资助:
    国家自然科学基金资助项目（82274117、82204710）; 国家中医药管理局高水平重点学科建设项目-临床中药学（zyyzdxk-2023257）

Prediction of Allopurinol-Induced Renal Injury Markers and Pharmacovigilance Based on ceRNA Network and Molecular Docking

GAO Fujun1, ZHANG Xiaomeng1,2, CHEN Lijuan1, CAI Haili1, LIU Xinlong1, ZHANG Bing1,2*   

  1. 1College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China;
    2Research Center for Pharmacovigilance and Rational Use of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China;
    3Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University
  • Received:2025-08-17 Online:2025-11-15 Published:2025-11-14

PDF (PC)

48

增强发表(附录)

1

摘要： 目的 预测别嘌醇（Allopurinol）肾脏损伤标志物,讨论别嘌醇联用中药的作用,为别嘌醇药物警戒提供新策略。方法 从GEO数据库芯片 GSE214358获取大鼠肾小管细胞正常组与别嘌醇处理转录组数据,使用R语言分析差异表达基因（DEGs）,进行Gene Ontology（GO）和 Kyoto Encyclopedia of Genes and Genomes（KEGG）富集分析及Protein-Protein Interaction Networks（PPI）蛋白互作分析,筛选关键DEGs。通过miRwalk、TargetScan、Starbase和miRDB数据库预测关键DEGs的靶向微小RNA（microRNA, miRNA）,使用Lncbase和Starbase数据库预测miRNA靶向的长链非编码RNA（Long Non-Coding RNA, LncRNA）,通过Cytoscape 构建 mRNA-miRNA-lncRNA 竞争性内源RNA（Competing Endogenouse RNA, ceRNA）调控网络,并结合分子对接验证别嘌醇及其活性代谢产物与关键DEGs的结合特性。结果 研究发现GSE214358数据芯片共1 649个DEGs,主要参与代谢缬氨酸、亮氨酸和异亮氨酸降解以及β-丙氨酸代谢等信号通路。经过PPI分析并使用CytoHubba得到10个关键DEGs,发现其中7个关键DEGs参与ceRNA网络,分别为BCKDHB、ALDH6A1、ACADM、HWGCL、ACAT1、IVD、OXCT1,靶向miRNA 128个,且均与lncRNA OIP5-AS1对应。通过分子对接验证发现BCKDHB与别嘌醇及氧嘌呤醇的结合特性最好,BCKDHB-miR-654-3p/miR-766-5p-OIP5-AS1轴在别嘌醇肾损伤中可能被显著激活。结论 BCKDHB-miR-654-3p/miR-766-5p-OIP5-AS1轴可能在别嘌醇肾脏损伤中发挥了重要作用,可作为早期诊断生物标志物,在处方前或用药早期发出预警,为别嘌醇的安全使用提供参考。

关键词: 别嘌醇, 药物性肾损伤, BCKDHB, ALDH6A1, ACADM, ceRNA网络, 分子对接, 中西药联用, 药物警戒

Abstract: Objective To predict the renal injury markers of allopurinol, study the effect of allopurinol combined with traditional Chinese medicine (TCM), and provide a new strategy for pharmacovigilance of allopurinol. Methods The transcriptome data on rat renal tubular cells from the normal group and from the allopurinol-treated group were obtained from the microarray (GSE214358) in the GEO database. R language was used to analyze the differentially expressed genes (DEGs). Enrichment analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) as well as protein-protein interaction (PPI) network analysis were conducted to screen key DEGs. Databases including miRwalk, TargetScan, starBase and miRDB were searched to predict the target microRNA (microRNA, miRNA) of the key DEGs. Lncbase and starBase were used to predict the long non-coding RNA (Long non-coding RNA, lncRNA) targeted by these miRNA. Cytoscape was used to construct the mRNA-miRNA-lncRNA competing endogenous RNA (competing endogenouse RNA, ceRNA) regulatory network. Additionally, molecular docking was performed to verify the binding properties of allopurinol and its active metabolites to the key DEGs. Results The GSE214358 data chip had a total of 1649 DEGs, mainly involved in such metabolic pathways as valine, leucine and isoleucine degradation and β-alanine metabolism. Via PPI analysis and CytoHubba, 10 key DEGs were obtained. It was found that 7 of the key DEGs were involved in the ceRNA network, namely BCKDHB, ALDH6A1, ACADM, HWGCL, ACAT1, IVD, and OXCT1, targeting 128 miRNA, all of which corresponded to lncRNA OIP5-AS1. Molecular docking verification found that BCKDHB had the best binding characteristics with allopurinol and oxypurinol. The BCKDHB-miR-654-3p/miR-766-5p-OIP5-AS1 axis might be significantly activated in allopurinol-induced renal injury. Conclusion The BCKDHB-miR-654-3p/miR-766-5p-OIP5-AS1 axis may play an important role in allopurinol-induced renal injury. It can potentially serve as an early diagnostic biomarker that gives warnings before prescription or in the early stage of medication, so it offers a new strategy for the safe administration of allopurinol. The rational combination of allopurinol with traditional Chinese medicine can enhance therapeutic effects and reduce toxicity, providing a crucial approach to the rational use of allopurinol.

Key words: Allopurinol, Drug-Induced Renal Injury, BCKDHB, ALDH6A1, ACADM, ceRNA Network, Molecular Docking, Combination of Traditional Chinese and Western Medicine, Pharmacovigilance

中图分类号: