Programmed cell death-related transcriptomic features are associated with aortic valve calcification progression: an integrated analysis of public datasets and clinical samples.

Background: Calcific aortic valve disease (CAVD) is an active, cell-mediated disorder lacking effective medical therapy. The contribution of programmed cell death (PCD) to disease progression remains insufficiently characterized. This study aimed to characterize PCD-related transcriptomic features during CAVD progression and identify candidate molecular indicators associated with disease severity. Methods: Transcriptomic datasets from aortic valve tissues were analyzed using differential expression, PCD activity scoring, weighted gene co-expression network analysis (WGCNA), Mfuzz clustering, and least absolute shrinkage and selection operator (LASSO) regression. A PCD-related gene signature was constructed and validated in an external cohort. Immune infiltration was profiled using Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT), and peripheral blood leukocyte samples from patients with aortic valve disease were used for quantitative real-time polymerase chain reaction (qRT-PCR) validation. Results: PCD-related gene set enrichment increased progressively across disease stages (P=0.01). Integrative multi-step screening identified four key genes- Conclusions: PCD-related transcriptomic enrichment was associated with aortic valve calcification severity and was accompanied by immune remodeling, although these changes may partly reflect overlapping inflammatory and cellular stress responses. The four-gene signature provides mechanistic insight into disease progression and represents a potential tool for molecular stratification and future therapeutic exploration.