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Background <p>Atherosclerosis remains a leading cause of cardiovascular morbidity and mortality despite advances in lipid-lowering therapy. The proprotein convertase subtilisin/kexin type 9 protein (PCSK9) was originally characterized for promoting degradation of the low-density lipoprotein receptor and raising circulating low-density lipoprotein cholesterol, but growing evidence shows that PCSK9 also participates directly in vascular inflammation and oxidative stress, bridging lipid dysregulation and immune activation.</p> Main body <p>PCSK9 amplifies vascular inflammation through several linked mechanisms. PCSK9 augments toll-like receptor 4/nuclear factor kappa B signaling, raising transcription and release of cytokines such as tumor necrosis factor alpha, and increasing adhesion molecule expression that promotes leukocyte recruitment. PCSK9 upregulates scavenger receptors, notably lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), and CD36, which enhances uptake of oxidized lipoprotein, foam cell formation and activation of the NLRP3 inflammasome. PCSK9 also promotes reactive oxygen species generation via NADPH oxidase and impairs nitric oxide biology, worsening endothelial dysfunction. Together these pathways form a self-amplifying loop in which oxidized lipoprotein and cytokines further increase PCSK9 expression. Clinical and preclinical data indicate that PCSK9 inhibitors markedly lower low-density lipoprotein cholesterol and can reduce some markers of plaque inflammation and oxidative stress, but its full therapeutic potential remains a subject of ongoing investigation.</p> Conclusion <p>PCSK9 functions as a molecular bridge between dyslipidemia and vascular inflammation; defining the precise molecular interactions and how different modes of PCSK9 inhibition affect these pathways may enable targeted anti-inflammatory strategies to complement lipid lowering and reduce residual cardiovascular risk.</p>

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PCSK9 molecular bridge between hyperlipidemia and vascular inflammation: novel insights into PCSK9-centered pathways in atherosclerosis: a comprehensive review

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月7日

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  • Muhammad A. Desouky,
  • Mohammed A. El-Magd,
  • Mohamed Abdelmeguid Mousa,
  • Abbas Hayat Mallick,
  • Delwar Khan,
  • Dina A. Desouky

摘要

Background

Atherosclerosis remains a leading cause of cardiovascular morbidity and mortality despite advances in lipid-lowering therapy. The proprotein convertase subtilisin/kexin type 9 protein (PCSK9) was originally characterized for promoting degradation of the low-density lipoprotein receptor and raising circulating low-density lipoprotein cholesterol, but growing evidence shows that PCSK9 also participates directly in vascular inflammation and oxidative stress, bridging lipid dysregulation and immune activation.

Main body

PCSK9 amplifies vascular inflammation through several linked mechanisms. PCSK9 augments toll-like receptor 4/nuclear factor kappa B signaling, raising transcription and release of cytokines such as tumor necrosis factor alpha, and increasing adhesion molecule expression that promotes leukocyte recruitment. PCSK9 upregulates scavenger receptors, notably lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), and CD36, which enhances uptake of oxidized lipoprotein, foam cell formation and activation of the NLRP3 inflammasome. PCSK9 also promotes reactive oxygen species generation via NADPH oxidase and impairs nitric oxide biology, worsening endothelial dysfunction. Together these pathways form a self-amplifying loop in which oxidized lipoprotein and cytokines further increase PCSK9 expression. Clinical and preclinical data indicate that PCSK9 inhibitors markedly lower low-density lipoprotein cholesterol and can reduce some markers of plaque inflammation and oxidative stress, but its full therapeutic potential remains a subject of ongoing investigation.

Conclusion

PCSK9 functions as a molecular bridge between dyslipidemia and vascular inflammation; defining the precise molecular interactions and how different modes of PCSK9 inhibition affect these pathways may enable targeted anti-inflammatory strategies to complement lipid lowering and reduce residual cardiovascular risk.