糖尿病铜死亡生物标志物的鉴定与药物筛选

Identification of cuproptosis biomarkers and drug screening in diabetes mellitus

目的探索糖尿病(diabetes mellitus,DM)铜死亡(Cuproptosis)生物标志物以及进行药物筛选。方法利用GEO数据库获取糖尿病GSE25724数据集作为训练集并筛选其差异表达基因,从文献获取19个铜死亡相关基因,两者取交集得到糖尿病铜死亡相关基因,对此基因进行验证(GSE23343与GSE20966作为测试集)。对DM铜死亡基因进行基因相关性分析和富集分析。使用DS BIOVIA Discovery Studio 2016软件对关键基因与所预测的化合物进行分子对接。结果共获得6个糖尿病相关的铜死亡基因(DBT、DLD、GLS、PDHB、NFE2L2和LIPT1),他们主要通过调控三羧酸循环的脂化、丙酮酸代谢、糖酵解糖质新生、HIF-1等信号通路而参与有机酸代谢分解、丙酮酸乙酰辅酶A的合成和氨基酸代谢等生物学过程。这6个基因中DLD、DBT、NFE2L2在测试集样本中差异表达显著,且有较好的诊断价值,分子对接显示DLD、DBT可以与叶酸,NFE2L2可与紫铆素,NFE2L2可与木犀草素有较高的结合能力。结论铜死亡相关基因DLD、DBT、NFE2L2在糖尿病的发生发展中起重要作用,本研究为糖尿病的发病机制及治疗研究提供数据支撑。

Objective To explore the biomarkers of cuproptosis in diabetes mellitus(DM)for drug screening.Methods The GEO database was used to obtain GSE25724 dataset of DM as a training set and screen its differentially expressed genes,and 19 cuproptosis-related genes were obtained from the literature.The intersection of the two was used to obtain cuproptosis-related genes in DM,which were then validated(GSE23343 and GSE20966 were used as a test set).Gene correlation and enrichment analyses were performed on cuproptosis-related genes in DM.Molecular docking of key genes with predicted compounds was performed using DS BIOVIA Discovery Studio 2016 software.Results A total of six diabetes-associated cuproptosis-related genes(DBT,DLD,GLS,PDHB,NFE2L2,and LIPT1)were obtained,and they were involved in biological processes such as metabolic catabolism of organic acids,synthesis of pyruvate-acetyl-coenzyme A and amino acid metabolism,mainly through the regulation of the signaling pathways of the tricarboxylic acid(TCA)cycle of lipidation,pyruvate metabolism,glycolytic glucose de novo,and HIF-1.Among these six genes,DLD,DBT and NFE2L2 were significantly differentially expressed in the test set samples and had good diagnostic value.Molecular docking showed that DLD and DBT could have a high binding capacity with folic acid,NFE2L2 with Butin,and NFE2L2 with Luteolin.Conclusion Cuproptosis-related genes DLD,DBT,and NFE2L2 play an important role in the occurrence and development of DM,and this study provides data support for the studies of the pathogenesis and treatment of DM.