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<p>Abdominal aortic aneurysm (AAA) is a progressive dilation of the abdominal aorta that can rupture and cause catastrophic internal bleeding, yet the mechanisms driving AAA remain poorly understood. Here we show that pyruvate dehydrogenase kinase 4 (PDK4), a key metabolic regulator, is upregulated in human and mouse AAA tissues. Deletion of <i>Pdk4</i> in vascular smooth muscle cells (VSMCs) significantly reduces AAA formation in male mice. Mechanistically, PDK4 promotes metabolic reprogramming in VSMCs, disrupts mitochondrial respiration, and activates the NLRP3 inflammasome and pyroptosis, thereby exacerbating vascular inflammation and AAA progression. Genetic deletion of <i>Pdk4</i> in VSMCs or pharmacological inhibition of NLRP3 attenuates AAA development in mice. These findings identify PDK4 as a driver of AAA and suggest that targeting PDK4 may represent a therapeutic strategy for this life-threatening disease.</p>

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PDK4 drives abdominal aortic aneurysm by promoting smooth muscle cell metabolic reprogramming and NLRP3-mediated pyroptosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月11日

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  • Li Zhao,
  • Xuefeng Lin,
  • Zhengqiang Zhu,
  • Ranxin Liu,
  • Lingna Zhao,
  • Xuekun Wu,
  • Mengru Zheng,
  • Rihua Huang,
  • Pengyu Zhou,
  • Fangze Huang,
  • Deshen Liu,
  • Chuanjie Niu,
  • Xiaoxia He,
  • Zean Wang,
  • Xin Li,
  • Jiale Li,
  • Shengping He,
  • Jun Lu,
  • Shaoyi Zheng,
  • Jiaguo Zhou,
  • Qinbao Peng,
  • Xiu Liu

摘要

Abdominal aortic aneurysm (AAA) is a progressive dilation of the abdominal aorta that can rupture and cause catastrophic internal bleeding, yet the mechanisms driving AAA remain poorly understood. Here we show that pyruvate dehydrogenase kinase 4 (PDK4), a key metabolic regulator, is upregulated in human and mouse AAA tissues. Deletion of Pdk4 in vascular smooth muscle cells (VSMCs) significantly reduces AAA formation in male mice. Mechanistically, PDK4 promotes metabolic reprogramming in VSMCs, disrupts mitochondrial respiration, and activates the NLRP3 inflammasome and pyroptosis, thereby exacerbating vascular inflammation and AAA progression. Genetic deletion of Pdk4 in VSMCs or pharmacological inhibition of NLRP3 attenuates AAA development in mice. These findings identify PDK4 as a driver of AAA and suggest that targeting PDK4 may represent a therapeutic strategy for this life-threatening disease.