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<p>Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in the molecular pathophysiology of the cardiorenal axis by facilitating the degradation of LDL receptors, which results in increased LDL cholesterol levels, inflammation, and fibrosis. PCSK9 is involved in activating various pathways, including NF-κB and the NLRP3 inflammasome, while simultaneously inhibiting PPAR and SIRT3. This dysregulation contributes to oxidative stress, apoptosis, and renal lipotoxicity through the impairment of megalin function. The resultant molecular processes lead to the secretion of proinflammatory cytokines such as IL-1β, IL-6, TNF-α, and NF-κB, which exacerbate fibrosis and tissue injury. The heightened activity of PCSK9 is associated with the accumulation of LDL in the kidneys, causing nephrotoxicity and dysfunction within the cardiorenal system. Notably, the inhibition or deficiency of PCSK9 has been shown to confer protective effects, mitigating inflammation, oxidative stress, and apoptosis in the cardiorenal axis. Consequently, targeting PCSK9 and its related pathways may pave the way for innovative therapeutic approaches aimed at reducing inflammation, oxidative stress, and apoptosis, thereby enhancing the clinical outcomes for individuals with cardiorenal dysfunction.</p> Graphical Abstract <p>This diagram highlights that PCSK9 has a pivotal role in cardiorenal syndrome as it promotes the degradation of LDL receptor in the liver, which elevates LDL-C levels and contribute to both atherosclerotic and glomerulosclerosis. It activates NF-κB/NLRP3-mediated inflammation, inhibits SIRT3/PPAR causing oxidative stress and apoptosis, and increased ENaC expression, resulting in sodium and water retention. These mechanisms collectively exacerbate cardiovascular and renal dysfunction, positioning PCSK9 as a vital therapeutic target in cardiorenal axis. </p>

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Molecular mechanisms of PCSK9 in cardiology: therapeutic implications and clinical impacts on the cardiorenal axis

  • 期刊论文

  • 发表日期：

    2026年1月2日

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  • Sandeep Kaur,
  • Drishti Panjwani,
  • Shareen Singh,
  • Souvik Banerjee,
  • Sukriti Wadehra,
  • Amritpal Kaur,
  • Thakur Gurjeet Singh

摘要

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in the molecular pathophysiology of the cardiorenal axis by facilitating the degradation of LDL receptors, which results in increased LDL cholesterol levels, inflammation, and fibrosis. PCSK9 is involved in activating various pathways, including NF-κB and the NLRP3 inflammasome, while simultaneously inhibiting PPAR and SIRT3. This dysregulation contributes to oxidative stress, apoptosis, and renal lipotoxicity through the impairment of megalin function. The resultant molecular processes lead to the secretion of proinflammatory cytokines such as IL-1β, IL-6, TNF-α, and NF-κB, which exacerbate fibrosis and tissue injury. The heightened activity of PCSK9 is associated with the accumulation of LDL in the kidneys, causing nephrotoxicity and dysfunction within the cardiorenal system. Notably, the inhibition or deficiency of PCSK9 has been shown to confer protective effects, mitigating inflammation, oxidative stress, and apoptosis in the cardiorenal axis. Consequently, targeting PCSK9 and its related pathways may pave the way for innovative therapeutic approaches aimed at reducing inflammation, oxidative stress, and apoptosis, thereby enhancing the clinical outcomes for individuals with cardiorenal dysfunction.

Graphical Abstract

This diagram highlights that PCSK9 has a pivotal role in cardiorenal syndrome as it promotes the degradation of LDL receptor in the liver, which elevates LDL-C levels and contribute to both atherosclerotic and glomerulosclerosis. It activates NF-κB/NLRP3-mediated inflammation, inhibits SIRT3/PPAR causing oxidative stress and apoptosis, and increased ENaC expression, resulting in sodium and water retention. These mechanisms collectively exacerbate cardiovascular and renal dysfunction, positioning PCSK9 as a vital therapeutic target in cardiorenal axis.