PCSK9 as a Potential Regulator of Endothelial Dysfunction: Mechanistic Insights and Future Directions.

The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) and its role in promoting the degradation of the low-density lipoprotein receptor (LDLR) has revolutionized lipid-lowering therapy, offering new therapy for patients with hypercholesterolemia. Notably, PCSK9 is now being explored for functions beyond lipid regulation. Emerging evidence implicates PCSK9 in vascular pathology by influencing endothelial dysfunction, inflammatory signaling, oxidative stress, and vascular homeostasis-potentially through LDLR-independent mechanisms. This review critically evaluates PCSK9's potential as a regulator of endothelial dysfunction, synthesizing findings from in vitro, in vivo, and clinical studies. While current PCSK9-targeted therapies, including monoclonal antibodies and siRNA-based agents, have demonstrated robust efficacy in lowering lipid levels and reducing cardiovascular risk, their direct effects on endothelial PCSK9 signaling remain unclear. On the other hand, novel approaches-such as peptide-based inhibitors, intracellular modulation, and natural compounds-resulted in new insights into endothelial-specific PCSK9 pathways. Overall, this review highlights the need to bridge experimental and clinical evidence by applying endothelial-focused models, multi-omics analyses, and functional vascular assessments to clarify the role of PCSK9 in endothelial dysfunction and to propose future strategies for cardiovascular interventions targeting PCSK9-mediated endothelial dysfunction.