PCSK9 as a Regulatory Network: Molecular Mechanisms, Therapeutic Targeting, and Herbal Modulation.

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a central regulator of cholesterol homeostasis through its role in promoting low-density lipoprotein receptor (LDLR) degradation and limiting hepatic low-density lipoprotein cholesterol (LDL-C) clearance. The clinical success of monoclonal antibodies and small interfering RNA (siRNA)-based therapies has established PCSK9 as an important therapeutic target. However, PCSK9 biology extends beyond its canonical role in LDLR degradation, with its expression and activity regulated through interconnected transcriptional, post-transcriptional, metabolic, and intracellular signaling mechanisms involving sterol regulatory element-binding protein-2 (SREBP-2), hepatocyte nuclear factor-1α (HNF-1α), microRNAs, and multiple signaling pathways. This regulatory complexity is illustrated by compensatory responses, including statin-induced PCSK9 expression, and by observations that changes in PCSK9 expression do not always directly predict overall metabolic outcomes. Current therapeutic strategies primarily target circulating PCSK9 or suppress its hepatic synthesis, whereas upstream and multi-level regulatory mechanisms remain less extensively explored. Herbal-derived compounds have emerged as potential multi-target modulators of the PCSK9 regulatory network, with experimental studies indicating that phytochemicals and plant extracts may influence PCSK9 through coordinated effects on transcriptional regulators, cellular signaling pathways, and LDLR expression. Nevertheless, the available evidence is heterogeneous, with substantial variation in experimental models, phytochemical composition, dosing strategies, and mechanistic endpoints. This review integrates current evidence on the molecular regulation of PCSK9, established and emerging therapeutic strategies, and herbal modulation across in vitro, in vivo, and in silico studies. Overall, the evidence supports a network-based interpretation of PCSK9 regulation and suggests that multi-target herbal modulation may provide a complementary strategy to conventional PCSK9-directed therapies by acting at multiple regulatory levels. However, the predominantly preclinical nature of the available evidence underscores the need for standardized phytochemical characterization, rigorous mechanistic validation, and well-designed clinical studies before therapeutic translation can be established.

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