SORT1 encodes sortilin, a type I transmembrane receptor that functions as both a sorting receptor in the Golgi compartment and a clearance receptor at the cell surface. The protein plays critical roles in cardiovascular health and lipid metabolism. SORT1 is strongly associated with cardiovascular disease risk, with genome-wide association studies identifying the 1p13.3 locus (containing SORT1) as linked to LDL-cholesterol levels, coronary artery disease, and calcific aortic stenosis 12. Mechanistically, sortilin regulates hepatic lipid metabolism through VLDL secretion and facilitates lysosomal degradation of CES1, which is crucial for triglyceride breakdown 3. The protein undergoes chaperone-mediated autophagy via recognition of KFERQ-like motifs, and disruption of this degradation pathway leads to impaired lipid homeostasis 3. In cardiovascular pathology, sortilin promotes calcific aortic valve disease by inducing valvular interstitial cell transformation into inflammatory myofibroblastic-osteogenic phenotypes, contributing to fibrosis and calcification 4. Additionally, SORT1 expression in vascular smooth muscle cells is critical for maintaining normal aortic wall function, with genetic variants providing protection against cardiovascular disease in cognitively healthy centenarians 56.