Computational identification of necroptosis-related hub genes and therapeutic targets in dilated cardiomyopathy via integrated analysis of bulk and single-cell RNA sequencing public cohorts

Dilated cardiomyopathy (DCM) is a prevalent myocardial disease with a grim poor prognosis, and its pathogenesis remains poorly understood. Necroptosis, a programmed cell death mechanism, is believed to be significantly involved in the pathogenesis of DCM. This study aimed to identify necroptosis-related hub genes associated with DCM and predict potential agents for DCM. All analyses exclusively utilized publicly available datasets from the Gene Expression Omnibus database. Differentially expressed genes were identified in the DCM dataset GSE128095. The least absolute shrinkage and selection operator and random forest algorithms were then employed to identify 5 necroptosis-related hub genes. A diagnostic model for DCM was constructed based on these hub genes, and the expression profiles of these genes across different myocardial cell populations were systematically analyzed using single-cell RNA sequencing data from GSE184899 dataset. Furthermore, the drug-gene interaction database was utilized to identify potential therapeutic candidates targeting these hub genes. A total of 17 necroptosis-related genes were identified, primarily associated with biological processes such as apoptosis, antiviral immune response, and autophagy, with a particular localization in lysosome/autophagy-related structures and membrane functional regions. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that these genes predominantly regulated the necroptosis and NOD-like receptor signaling pathways. Five necroptosis-related hub differentially expressed genes (CAPN1, SLC25A5, IFNGR2, CAMK2A, and BIRC3) were pinpointed. The DCM diagnostic model based on these 5 hub genes demonstrated excellent diagnostic efficacy. These hub genes displayed distinct expression profiles across various cardiac cell types. Notably, the upregulated hub genes in DCM including SLC25A5, IFNGR2, and CANP1, exhibited increased expression in multiple cardiac cell types, encompassing cardiomyocytes, smooth muscle cells, and endothelial cells. Conversely, the downregulated gene CAMK2A in DCM displayed a specific expression preference in fibroblasts. Finally, Calpeptin was predicted as a potential therapeutic agent for DCM. This study computationally identified 5 hub genes associated with necroptosis in DCM, developed a diagnostic model, and proposed one potential therapeutic drug, providing novel insights for the diagnosis and management of DCM.