Juncheng Jiang, Lei Chen, Hao Lin, Fei Liang
Department of Cardiovascular Surgery, Shandong Provincial Hospital, Shandong Fist Medical University, No. 324, Jingwu Road, 250021, Jinan, China.
Hereditas. 2025 Aug 7;162(1):152. doi: 10.1186/s41065-025-00521-5.
Heart failure (HF) is a complex clinical condition characterized by impaired cardiac function and progressive structural remodeling. To elucidate the molecular mechanisms driving HF, this study aimed to identify key regulatory hub genes, explore their functional relevance, and assess their diagnostic and therapeutic potential.
Four public microarray datasets (GSE161472, GSE147236, GSE116250, and GSE46224) were retrieved from the Gene Expression Omnibus (GEO) database. Differential expression analysis using the limma package in R identified Differentially expressed genes (DEGs), which were further analyzed via Venn diagrams, STRING PPI networks, and Cytoscape's CytoHubba plugin to determine top hub genes. RT-qPCR and Western blotting were used to validate gene expression in HF and normal cardiomyocyte cell lines. Functional assays (proliferation, colony formation, and wound healing) were conducted following overexpression of COL9A1 and MTIF3. miRNA regulation and immune cell infiltration were analyzed using TargetScan and CIBERSORT, respectively. Enrichment analysis was performed via DAVID, and drug prediction was conducted using DGIdb.
Four hub genes-COL9A1, MTIF3, MRPS25, and HMGN1-were consistently downregulated in HF and exhibited high diagnostic potential (AUC > 0.8). Overexpression of COL9A1 and MTIF3 significantly reduced cell proliferation, colony formation, and migration in HF cell lines. Immune infiltration analysis revealed strong negative correlations between hub gene expression and various immune cell types. Drug prediction identified Milrinone as a potential therapeutic candidate targeting COL9A1.
COL9A1, MTIF3, MRPS25, and HMGN1 emerge as critical biomarkers and regulators in HF, offering promising avenues for diagnosis, mechanistic understanding, and targeted therapy development.
心力衰竭（HF）是一种复杂的临床病症，其特征为心脏功能受损和进行性结构重塑。为了阐明驱动HF的分子机制，本研究旨在识别关键调控枢纽基因，探索其功能相关性，并评估其诊断和治疗潜力。
从基因表达综合数据库（GEO）中检索了四个公共微阵列数据集（GSE161472、GSE147236、GSE116250和GSE46224）。使用R语言中的limma软件包进行差异表达分析，以识别差异表达基因（DEG），并通过维恩图、STRING蛋白质-蛋白质相互作用网络和Cytoscape的CytoHubba插件进一步分析，以确定顶级枢纽基因。采用逆转录定量聚合酶链反应（RT-qPCR）和蛋白质免疫印迹法验证HF和正常心肌细胞系中的基因表达。在过表达COL9A1和MTIF3后进行功能测定（增殖、集落形成和伤口愈合）。分别使用TargetScan和CIBERSORT分析miRNA调控和免疫细胞浸润。通过DAVID进行富集分析，并使用DGIdb进行药物预测。
四个枢纽基因——COL9A1、MTIF3、MRPS25和HMGN1——在HF中始终下调，并具有较高的诊断潜力（曲线下面积>0.8）。COL9A1和MTIF3的过表达显著降低了HF细胞系中的细胞增殖、集落形成和迁移。免疫浸润分析显示枢纽基因表达与多种免疫细胞类型之间存在强烈的负相关。药物预测确定米力农是一种靶向COL9A1的潜在治疗候选药物。
COL9A1、MTIF3、MRPS25和HMGN1成为HF中的关键生物标志物和调节因子，为诊断、机制理解和靶向治疗开发提供了有前景的途径。
