Decoding and Targeting Coordinated CDKN1A and CDKN2A Senescence Programs in ECM-Dominant Cardiovascular Pathologies

Cellular senescence is a hallmark of aging and an emerging therapeutic target; however, its role as a context-specific driver of disease remains incompletely defined, and senolytic therapies have shown inconsistent clinical benefit. Here, we identify extracellular matrix (ECM)-dominant pathologies as a major class of senescence-driven disease, characterized by inflammation, matrix degeneration, and progressive tissue dysfunction. Using integrated single-cell transcriptomics, spatial profiling, and multiplex imaging across human specimens and murine models, we demonstrate that senescent fibroblasts, rather than canonical myofibroblasts, constitute the principal disease-driving cell state in myxomatous mitral valve disease (MMVD) and related conditions. These cells exhibit coordinated CDKN1A inflammatory and CDKN2A ECM-remodeling programs that form a feed-forward circuit linking immune activation to matrix disorganization and functional decline. Senescence extends beyond fibroblasts to endothelial and immune compartments, establishing a multicellular senescent milieu that reinforces intercellular crosstalk and disease progression. Senolytic treatment (dasatinib plus quercetin or fisetin) restores ECM architecture and improves cardiac function, outperforming pathway-specific anti-inflammatory and antifibrotic approaches. Cross-disease analyses further reveal conservation of this coordinated CDKN1A/CDKN2A senescence programs across multiple ECM-dominant cardiovascular diseases, including aortic aneurysm and calcific valve disease. Notably, in vivo single-cell transcriptomic profiling following multiple senolytic treatments provides whole-transcriptome resolution of context-dependent cellular responses. Collectively, these findings establish context-specific senescence as a central organizing mechanism in ECM-dominant diseases and support a shift from generalized anti-aging strategies toward precision senolytic prevention or therapy. Given that valvular and aortic diseases affect millions and increase markedly with age to a prevalence comparable to major cancers, these results indicate a potential solution to a substantial and underrecognized clinical burden.