Post-transcriptional targeting of PCSK9 by microRNAs: From mechanisms to therapeutic potential

Abstract

The reduction of serum low-density lipoprotein cholesterol (LDL-C) remains a cornerstone in the prevention and management of atherosclerotic cardiovascular disease (ASCVD). Over the past decades, substantial progress has been made in elucidating the molecular mechanisms regulating cholesterol homeostasis, leading to the development of effective LDL-lowering therapies. A pivotal advancement in this field was the identification of proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease that plays a critical role in lipid metabolism. PCSK9 promotes the degradation of hepatic LDL receptors (LDL-R), thereby impairing the clearance of circulating LDL-C. The discovery that loss-of-function mutations in PCSK9 confer protection against cardiovascular events has spurred the development of PCSK9-targeted therapies, particularly monoclonal antibodies, which have demonstrated robust efficacy in reducing LDL-C levels and cardiovascular risk. Despite these clinical successes, the intricate regulatory networks governing PCSK9 expression, especially at the post-transcriptional level, remain incompletely understood. Emerging evidence implicates microRNAs (miRNAs) as key modulators of lipid metabolism, including the regulation of PCSK9. These small, non-coding RNAs orchestrate complex gene regulatory circuits and have the potential to fine-tune PCSK9 expression, offering novel therapeutic avenues beyond current pharmacological inhibitors. This review critically examines the current understanding of miRNA-mediated regulation of PCSK9, highlights key miRNAs implicated in this process, and discusses their potential as therapeutic targets or biomarkers in the context of dyslipidemia and cardiovascular disease. Unraveling the interplay between miRNAs and PCSK9 may pave the way for next-generation lipid-lowering strategies with enhanced specificity and efficacy.