Mechanisms of action and therapeutic potential of PCSK9-regulating drugs

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) metabolism and is a key target for cardiovascular therapies. It also plays roles in inflammation, cancer, and metabolic disorders, prompting interest in repurposing PCSK9-targeting drugs for non-lipid conditions.

This review comprehensively summarizes PCSK9-regulating medications, delves into their mechanisms of action, and explores their increasingly expanding therapeutic potential across multiple organ systems, such as the liver, immune system, small intestine, heart, brain, and pancreas.

A comprehensive literature search was carried out in databases such as PubMed, with keywords like 'PCSK9 inhibitors', 'lipid metabolism', 'liver', 'immune system', 'neoplasms' and 'PCSK9-related diseases'. The search was meticulously designed to cover relevant research extensively. Only those studies that delved into the molecular mechanisms underlying PCSK9 regulation and the practical clinical applications of PCSK9-targeting therapies were selected for inclusion.

PCSK9-regulating drugs, encompassing monoclonal antibodies, small peptides, antisense oligonucleotides, small interfering RNAs, and vaccines, modulate PCSK9 expression or activity at different levels. These drugs are effective in lowering LDL-C levels and demonstrate potential benefits in the treatment of inflammation, non-alcoholic fatty liver disease, renal lipotoxicity, and various metabolic disorders. They mainly exert their effects by controlling PCSK9 gene transcription, influencing mRNA translation, and blocking the interaction between PCSK9 and LDL-R.

PCSK9-regulating drugs hold great promise for treating a diverse array of diseases. Future research should focus on optimizing their application in personalized therapies that target multiple pathways.