Multilayer regulation of osteogenic reprogramming in human aortic valve interstitial cells in calcific aortic valve disease

Calcific aortic valve disease (CAVD) is an active fibrocalcific disorder in which human aortic valve interstitial cells (hVICs) undergo heterogeneous osteogenic reprogramming. This narrative review provides an hVIC-centered synthesis of four interacting regulatory layers: pathological microenvironmental cues, intracellular signaling, non-coding RNA regulation, and cellular heterogeneity. Lipid dysregulation, inflammation, hypoxia, oxidative and metabolic stress, cellular senescence, and abnormal mechanical loading alter hVIC behavior through interconnected developmental, inflammatory, metabolic, and mechanosensitive pathways. Non-coding RNAs add post-transcriptional and epigenetic regulation, although many proposed axes remain incompletely validated. Single-cell transcriptomic studies further identify distinct disease-associated hVIC states and challenge a universal linear transition from quiescent to myofibroblast-like and osteogenic cells. We compare conventional and advanced experimental models and evaluate emerging therapeutic strategies according to the strength of human, functional, and translational evidence. Current data support a context- and stage-dependent network rather than a single dominant pathway. Integrating human valve tissue, cell-state-resolved analyses, complementary disease models, clinically meaningful endpoints, and targeted delivery may improve biomarker development and support disease-modifying strategies for CAVD.