Identification of diagnostic and therapeutic roles of programmed cell death–related proteins in dilated cardiomyopathy: a multi-omics and experimental validation study

Dilated cardiomyopathy (DCM) is a clinically heterogeneous cardiac disorder characterized by ventricular dilation and systolic dysfunction, with limited options for mechanism-based diagnosis and targeted therapy. Programmed cell death (PCD), encompassing apoptosis, ferroptosis, pyroptosis, and other regulated mechanisms, has been implicated in the pathogenesis of DCM, yet its diagnostic and therapeutic relevance remains incompletely understood. Here, we performed an integrative multi-omics analysis combining bulk and single-cell RNA sequencing datasets to identify PCD-related molecular features associated with DCM. Through differential gene expression, WGCNA, and six machine learning algorithms, eight core genes (AGTR2, GLI2, HRK, IL10, NQO1, NT5E, SFRP1, and STAT4) were identified and used to construct a predictive model evaluated across five independent cohorts. Immune infiltration and consensus clustering revealed two distinct molecular subtypes with differential immune-metabolic signatures. Single-cell analysis demonstrated cell-type-specific expression, particularly in fibroblasts and immune cells. Drug-gene interaction mapping and molecular docking highlighted decitabine and folic acid as potential therapeutic candidates. Expression of key genes was partially validated at the mRNA and protein levels in both human and mouse myocardium. Notably, given that most transcriptomic datasets represent advanced-stage disease, these findings may reflect shared molecular features of cardiac remodeling rather than early disease-specific mechanisms. This study provides insights into PCD-associated molecular alterations in DCM and offers a basis for future research into molecular stratification and therapeutic targeting.