Vascular calcification, a multifactorial condition associated with aging, chronic kidney disease, and diabetes, is a major cause of cardiovascular mortality. The process is driven by the osteogenic conversion of vascular smooth muscle cells (VSMCs). This review summarizes recent advances in the interconnected mechanisms that govern this process. The focal points of this review include metabolic reprogramming (with an emphasis on polyamine metabolism and metabolite signaling), the synergistic interplay between mitochondrial dysfunction and ferroptosis, and the epigenetic stabilization of the osteogenic phenotype (comprising histone modifications, DNA methylation, and non-coding RNAs). These cell-autonomous changes are amplified by pathological intercellular communication, particularly via extracellular vesicles and bidirectional endothelial-VSMC crosstalk, forming a self-perpetuating pathological network. In accordance with this framework, we hereby present several emerging therapeutic paradigms, including molecular glues for biased G protein-coupled receptor (GPCR) signaling, targeted protein degradation (TPD), ferroptosis inhibition, repurposed drugs, and gene editing. A further aspect of our research encompasses the evaluation of investigational agents that are currently undergoing clinical trials. Examples of such agents include SNF472 and ataciguat. Finally, we address key translational challenges and propose future directions for developing effective, multi-targeted interventions.
Keywords: Epigenetic regulation; Ferroptosis; Intercellular communication; Metabolic reprogramming; Therapeutic strategies; Vascular calcification.
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