昼夜节律和代谢途径在抑郁症中的角色:生物标志物的发现与新药物的预测

Roles of circadian rhythm and metabolic pathways in depression:identifying biomarkers and predicting novel therapeutic compounds

目的探讨抑郁症相关的生物标志物及潜在的药物,以期改善抑郁症症状,提高患者生活质量。方法于2022年11月—2024年1月,下载并分析Gene Expression Omnibus数据库中抑郁症患者和健康志愿者的表达谱,对其进行差异表达分析后得到差异表达基因,然后进行基因的富集分析,再进行蛋白质相互作用网络的构建,最后运行Cytoscape软件的插件Cytohubba找到其潜在的关键基因,并进行药物预测。结果通过差异表达分析,共找到110个差异表达基因(上调74个,下调36个)。蛋白质相互作用网络筛选出10个关键基因,差异表达分析显示其中8个基因(CPA3、HDC、IL3RA、ENPP3、PTGDR2、VTN、SPP1和SERPINE1)在健康志愿者和抑郁症患者之间的表达水平存在差异(P<0.05)。差异表达基因富集分析显示,上调基因显著富集于昼夜节律、烟酸和烟酰胺代谢、嘧啶代谢等通路,下调基因则主要富集在细胞外基质-受体相互作用、白细胞介素-17信号通路等通路。使用韦恩图获得了6个重叠验证基因(SALL2、AKAP12、GCSAML、CPA3、FCRL3和MS4A3),单细胞测序分析表明,这些基因在星形胶质细胞和神经细胞中表达显著。孟德尔随机化分析结果显示,FCRL3基因在抑郁症发生中可能具有重要作用。药物预测分析揭示了多种药物(如头孢替安、骆驼蓬醇、林可霉素、病毒唑等)具有潜在的抗抑郁作用。结论昼夜节律通路、烟酸和烟酰胺代谢通路、嘧啶代谢通路可能是抑郁症患者发病的潜在致病机制,骆驼蓬醇可能是抑郁症潜在的治疗药物。

Objective To explore depression-related biomarkers and potential therapeutic drugs in order to alleviate depression symptoms and improve patients’quality of life.Methods From November 2022 to January 2024,gene expression profiles of depression patients and healthy volunteers were downloaded from the Gene Expression Omnibus database.Differential expression analysis was performed to identify differentially expressed genes.Enrichment analysis of these genes was conducted,followed by the construction of a protein-protein interaction network.Finally,Cytoscape software with the Cytohubba plugin was used to identify potential key genes,and drug prediction was performed.Results Through differential expression analysis,a total of 110 differentially expressed genes(74 upregulated and 36 downregulated)were identified.Protein-protein interaction network identified 10 key genes,and differential expression analysis showed that 8 of these genes(CPA3,HDC,IL3RA,ENPP3,PTGDR2,VTN,SPP1,and SERPINE1)exhibited significant differences in expression levels between healthy volunteers and patients with depression(P<0.05).Enrichment analysis revealed that the upregulated genes were significantly enriched in pathways related to circadian rhythm,niacin and nicotinamide metabolism,and pyrimidine metabolism,while the downregulated genes were primarily enriched in extracellular matrix-receptor interaction and interleukin-17 signaling pathways.Six overlapping verification genes(SALL2,AKAP12,GCSAML,CPA3,FCRL3,and MS4A3)were obtained across two datasets using the Wayn diagram.Single-cell sequencing analysis indicated that these genes were significantly expressed in astrocytes and neurons.Mendelian randomization analysis suggested that the FCRL3 gene might play a critical role in the development of depression.Drug prediction analysis revealed several potential antidepressant agents,such as cefotiam,harmol,lincomycin,and ribavirin.Conclusions Circadian rhythm,nicotinate and nicotinamide metabolism,and pyrimidine metabolism pathways may represent potential pathogenic mechanisms in depression.Harmol may be a potential therapeutic drug for the treatment of depression.