Regulatory mechanisms of hepatocyte PCSK9 expression: translating mechanistic insights into potential nutraceuticals

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a critical regulator of cholesterol metabolism in hepatocytes with profound implications for cardiovascular health. This review explores the intricate regulatory network that controls hepatic PCSK9 expression and explores how these molecular insights can be translated into nutraceutical applications. The precise control of PCSK9 involves complex interactions among transcription factors, signaling pathways, epigenetic modifications, and post-transcriptional mechanisms. Although pharmaceutical PCSK9 inhibitors demonstrated remarkable efficacy, their high cost has stimulated interest in natural alternatives. Bioactive compounds such as berberine, piceatannol, gallic acid, and organosulfur derivatives from garlic have demonstrated the ability to modulate PCSK9 expression through diverse mechanisms, often targeting the same molecular pathways as conventional drugs. These nutraceuticals not only inhibit PCSK9 but also enhance the expression and activity of the low-density lipoprotein receptor, offering a promising approach to reduce cardiovascular risk with potentially fewer side effects and greater accessibility. Understanding the precise mechanisms of these natural compounds advances the development of targeted dietary strategies to complement conventional pharmacotherapy in the treatment of hypercholesterolemia.