The role of sortilin in cardiovascular calcification: mechanisms and therapeutic potential

Cardiovascular calcification is a common pathological feature driving cardiovascular morbidity and mortality. Although traditionally viewed as a passive degenerative process, current evidence demonstrates that calcification is an actively regulated, cell-driven phenomenon involving osteogenic differentiation, inflammation, and metabolic disturbances. Sortilin (encoded by SORT1), a multi-ligand intracellular trafficking receptor, has recently emerged as a critical molecular mediator linking metabolic risk factors-such as dyslipidemia, diabetes, hypertension, and chronic kidney disease-to pro-calcific cellular responses. In addition, sortilin also plays a versatile role by directly participating in the regulation of the phenotypic transformation of vascular smooth muscle cells and valve interstitial cells. This review provides a comprehensive synthesis of SORT1 biology in calcification-related risk states, delineates mechanistic insights into its specific roles in vascular and valve tissues, and discusses translational opportunities and challenges for targeting SORT1 in the prevention and treatment of cardiovascular calcification.