The pleiotropic effects of PCSK9 in cardiovascular diseases beyond cholesterol metabolism

Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality globally, with elevated low-density lipoprotein cholesterol (LDL-C) levels being a major risk factor. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in regulating LDL-C levels by promoting the degradation of hepatic low-density lipoprotein receptors (LDLR) responsible for clearing LDL-C from the circulation. PCSK9 inhibitors are novel lipid-modifying agents that have demonstrated remarkable efficacy in reducing plasma LDL-C levels and decreasing the incidence of CVD. However, the broader clinical impacts of PCSK9 functions beyond cholesterol metabolism, including both desired and undesired effects from therapeutic PCSK9 inhibition, underscore the urgent necessity to elucidate the underlying mechanisms. Recent studies have shown that local PCSK9 in the vascular system can interact with other receptors such as CD36, LRP-1, and ABCA1. This provides new evidence supporting the potential contribution of PCSK9 to CVD through LDLR-independent signaling pathways. Therefore, this review aimed to outline the diverse effects of PCSK9 on CVD and discuss the underlying mechanisms in non-cholesterol-related processes, which will provide a rational basis for its long-term pharmacological inhibition in the clinic.