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Life sciences · Journal article
European Journal of Clinical Investigation · October 1, 2026
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BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a pivotal regulator of cholesterol homeostasis, primarily known for inducing the degradation of the low-density lipoprotein receptor (LDLR). Beyond this classical pathway, PCSK9 exerts complex pleiotropic effects and interacts with various lipoproteins, contributing to cardiovascular and metabolic pathologies. This review synthesizes current knowledge on PCSK9 biology, its multi-organ implications and evolving therapeutic strategies. METHODS: This narrative review summarizes current evidence from experimental, translational and clinical studies on PCSK9 biology and therapeutics. The literature examined includes studies on PCSK9 transcriptional regulation, post-translational modifications, interactions with lipoproteins and the clinical development of established and emerging PCSK9-targeting therapies. RESULTS: PCSK9 activity is modulated by several transcription factors (e.g., SREBP2, HNF1α) and post-translational processes such as furin cleavage and sulfation. Clinically, elevated PCSK9 levels are linked to atherosclerosis progression, heart failure and adverse outcomes in infectious diseases and certain malignancies. Monoclonal antibodies (alirocumab, evolocumab) and siRNA (inclisiran) consistently reduce LDL-C by 50%-60%. Emerging approaches include oral inhibitors which may broaden access to PCSK9-targeting therapy, and CRISPR-based gene-editing strategies (e.g., VERVE-102), which aim to achieve sustained LDL-C lowering after a single treatment. CONCLUSIONS: PCSK9 is a multifaceted protein with roles extending far beyond LDL-C regulation. Understanding its diverse interactions is crucial for optimizing treatment in cardiovascular disease and potentially expanding its therapeutic application to metabolic and infectious conditions.