Mothers against decapentaplegic homolog 4 as a proteomic hub in vascular remodeling and residual cardiovascular risk

Translational cardiovascular medicine increasingly relies on systems-level approaches to uncover therapeutic targets that bridge molecular mechanisms and clinical outcomes. Recent proteomic analyses in experimental myocardial infarction models highlight how modulation of multiple protein networks can confer cardioprotection, emphasizing the complexity of post-infarction remodeling. Among this systems framework, mothers against decapentaplegic homolog 4 (SMAD4) has emerged as a pivotal mediator of transforming growth factor-β/bone morphogenetic protein signaling, integrating hemodynamic forces with endothelial, smooth muscle, and extracellular matrix responses. Experimental evidence demonstrates that SMAD4 governs endothelial mechanotransduction, vascular smooth muscle cell phenotype, fibrosis, and inflammation, while its loss promotes vascular instability, arteriovenous malformations and pulmonary vascular remodeling. High-throughput proteomics highlights SMAD4 as a network hub regulating cytoskeletal organization, oxidative stress, and extracellular matrix dynamics, providing mechanistic insight into processes contributing to plaque vulnerability and residual cardiovascular risk. Although not yet validated as a circulating biomarker, SMAD4 expression in vascular and immune cells may complement established markers such as low-density lipoprotein cholesterol and high-sensitivity C-reactive protein when integrated within multi-marker proteomic and artificial intelligence-assisted risk models. Therapeutically, cell-specific SMAD4 modulation, RNA-based strategies, and targeted interference with upstream signaling represent promising avenues for precision cardiology.