Identification of disease-associated gene expression signatures for mechanistic insights and drug prediction in dilated cardiomyopathy-induced heart failure

Dilated cardiomyopathy (DCM)-induced heart failure (HF) remains a major global health burden, highlighting the need to identify disease-associated molecular signatures and potential therapeutic targets. In this study, we performed differential expression analysis and weighted gene co-expression network analysis (WGCNA) on the GSE141910 dataset, which identified 138 genes associated with DCM-induced HF. These were further refined to 48 candidate genes using support vector machine-recursive feature elimination (SVM-RFE). Protein-protein interaction (PPI) network analysis revealed 10 hub genes, and external validation identified four core genes—MFAP4, CCDC80, LTBP2, and COL16A1—that were consistently upregulated in DCM-induced HF. Single-cell and functional enrichment analyses indicated that these genes are predominantly expressed in cardiac fibroblasts and may contribute to myocardial fibrosis by activation of the NOTCH signaling pathway. Drug screening suggested beta-naphthoflavone as a potential therapeutic compound. In vivo validation confirmed the upregulation of the core genes through RT-qPCR, western blot, and immunohistochemistry in an isoproterenol (ISO)-induced HF mouse model. In summary, MFAP4, CCDC80, LTBP2, and COL16A1 represent disease-associated transcriptional signatures and potential therapeutic targets for DCM-induced HF, offering novel insights into disease mechanisms and treatment strategies.