通过生物信息学分析、分子对接和实验验证相结合的方法鉴定与代谢综合征相关的心肌缺血再灌注损伤的诊断基因。

Identification of diagnostic genes for myocardial ischemia reperfusion injury associated with metabolic syndrome through the integration of bioinformatics analysis, molecular docking and experimental validation.

作者信息

Liu Shufang, Zhang Yan, Zhao Yanan, Wu Ping, Tian Shouyuan, Pang Han-Qing, Wu Zhifang, Li Sijin

机构信息

Department of Nuclear Medicine, First Hospital of Shanxi Medical University, Taiyuan, China.

Collaborative Innovation Center for Molecular Imaging of Precision Medicine, Shanxi Medical University, Taiyuan, China.

出版信息

Front Immunol. 2025 May 29;16:1567572. doi: 10.3389/fimmu.2025.1567572. eCollection 2025.

BACKGROUND

Metabolic dysregulation in metabolic syndrome (MetS) exacerbates myocardial ischemia-reperfusion injury (MIRI). This study aimed to identify diagnostic biomarkers and therapeutic candidates for MetS-associated MIRI.

METHODS

Three MIRI and two MetS datasets from GEO were analyzed using differential expression analysis, WGCNA, and machine learning (LASSO/SVM-RFE). Hub genes were validated via qRT-PCR in hypoxia-induced H9C2 cells. Drug candidates were predicted via PPI networks, CTD, and molecular docking, followed by experimental evaluation of dexamethasone.

RESULTS

Five hub genes-DAK, GTF3C5, KCNMB1, TRAF1, and ZNF692-were identified, with distinct expression patterns (DAK/GTF3C5 downregulated; KCNMB1/TRAF1/ZNF692 upregulated). These genes were enriched in immune-related pathways, and their diagnostic performance was robust (AUCs: 0.875-0.969). Dexamethasone downregulated KCNMB1/TRAF1/ZNF692 and reduced apoptosis in H9C2 cells.

CONCLUSION

This study reveals immune-metabolic dysregulation as a key driver of MetS-MIRI, proposes five biomarkers for diagnosis, and highlights dexamethasone as a promising therapeutic candidate.

背景

代谢综合征（MetS）中的代谢失调会加剧心肌缺血再灌注损伤（MIRI）。本研究旨在确定MetS相关MIRI的诊断生物标志物和治疗候选物。

方法

使用差异表达分析、加权基因共表达网络分析（WGCNA）和机器学习（LASSO/支持向量机递归特征消除法，SVM-RFE）对来自基因表达综合数据库（GEO）的三个MIRI数据集和两个MetS数据集进行分析。通过qRT-PCR在缺氧诱导的H9C2细胞中验证枢纽基因。通过蛋白质-蛋白质相互作用（PPI）网络、综合毒物数据库（CTD）和分子对接预测药物候选物，随后对地塞米松进行实验评估。

结果

确定了五个枢纽基因——二磷酸腺苷激酶（DAK）、通用转录因子3C5（GTF3C5）、钾电压门控通道亚家族M成员1（KCNMB1）、肿瘤坏死因子受体相关因子1（TRAF1）和锌指蛋白692（ZNF692），它们具有不同的表达模式（DAK/GTF3C5下调；KCNMB1/TRAF1/ZNF692上调）。这些基因富集于免疫相关途径，其诊断性能良好（曲线下面积：0.875 - 0.969）。地塞米松下调KCNMB1/TRAF1/ZNF692并减少H9C2细胞中的细胞凋亡。