LDL receptor-independent mechanisms of proprotein convertase subtilisin/kexin type 9 in cardiovascular pathophysiology

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a pivotal regulator of lipid metabolism and a validated therapeutic target in cardiovascular disease (CVD). While its canonical role in mediating low-density lipoprotein receptor (LDLR) degradation underpins its cholesterol-lowering effects, emerging evidence highlights diverse LDLR-independent actions that contribute to cardiovascular pathology. PCSK9 exerts pro-inflammatory, pro-atherosclerotic, pro-thrombotic, and cardiotoxic effects and promotes valvular calcification-thereby influencing vascular, myocardial, and structural heart disease beyond lipid regulation. This review delineates these non-canonical mechanisms, emphasizing PCSK9's roles in vascular inflammation, atherosclerosis, thrombosis, regulated cardiomyocyte death, and calcific aortic valve disease (CAVD). We also address key unresolved questions regarding the "efficacy gap" between pharmacological inhibition and lifelong genetic deficiency and examine the translational implications for next-generation inhibitors, including small molecules, vaccines, and gene-editing therapies. A deeper understanding of PCSK9's pleiotropic functions may inform precision strategies to achieve cardiovascular protection extending beyond LDL-C lowering.