PCSK9 in peripheral arterial disease: Mechanisms and therapeutic perspectives

This narrative review comprehensively examines the multifaceted roles of proprotein convertase subtilisin/kexin type 9 (PCSK9) in peripheral arterial disease (PAD). PCSK9, a key enzymatic regulator of lipid metabolism, binds to low-density lipoprotein receptors (LDLRs) and promotes their degradation, thereby increasing plasma low-density lipoprotein cholesterol (LDL-C) levels. This mechanism establishes PCSK9 as a critical driver of atherosclerosis and PAD. Emerging evidence indicates that the role of PCSK9 in PAD extended beyond its traditional lipid-modulating functions. Specifically, PCSK9 gene polymorphisms have been shown to significantly increase PAD susceptibility, while elevated plasma PCSK9 is an independent PAD risk factor and correlates positively with disease severity. Mechanistic studies revealed that PCSK9 directly participated in vascular pathological processes through multiple pathways, some of which are independent of LDLR-mediated effects. Current clinical applications have demonstrated that PCSK9 inhibitors confer clinically meaningful therapeutic benefits in PAD patients, including reduced risks of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). In particular, some of these clinical benefits may be attributed to improvements in endothelial function and microcirculatory perfusion. However, the therapeutic strategies involving PCSK9 inhibitors face persistent challenges, such as determining optimal dosing timelines, assessing long-term safety, and exploring synergies with other therapies. Future studies should prioritize large-scale randomized controlled trials to elucidate the molecular mechanisms underlying PCSK9's roles in vascular calcification and inflammatory microenvironments. Additionally, advancing the precision interventions targeting PCSK9 is essential for advancing comprehensive management approaches for PAD.