Lowering LDL cholesterol by PCSK9 inhibition: a new era of gene silencing, RNA, and alternative therapies.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) discovery has added a new paradigm to our understanding of cholesterol homeostasis and lipid metabolism. Since its discovery, PCSK9 inhibitors have become a widely investigated therapeutic class for lipid management in cardiovascular diseases and hypercholesterolemia. Scientists have explored different approaches for PCSK9 inhibition, such as monoclonal antibodies (mAbs), gene silencing and gene editing techniques, vaccines, mimetic peptides, and small molecules. European Medicines Agency (EMA) and United States Food and Drug Administration (US FDA) have approved only three PCSK9 inhibitors, including two monoclonal antibodies and one small interfering ribonucleic acid (siRNA). Despite the efficacy of approved large molecules, high costs and the need for regular injection have limited their adherence to the patient. This review aims to provide an understanding of PCSK9's function in Low-Density Lipoprotein Cholesterol (LDL-C) management, its current treatment, recent advancements, and potential future development of small molecules in the class of PCSK9 inhibitors.