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

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.

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Publication Details

Journal
Nature Communications
Published
2026-04-11
DOI
https://doi.org/10.1038/s41467-026-71610-w
Primary Topic
Aortic aneurysm repair treatments
Type
article
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article

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

Peitao Zhou, Shuai He, Zean Wang, Chuanjie Niu et al.
Nature Communications
Aortic aneurysm repair treatments
article

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

Peitao Zhou, Shuai He, Zean Wang, Chuanjie Niu, Fan Huang, Rihua Huang, Xuekun Wu, Zhengqiang Zhu, Xiu Liu, Qinbao Peng, MengRu Zheng, Ranxin Liu, Xiaoxia He, Lingna Zhao, Jiale Li, Li Zhao, Shaoyi Zheng, Xin Li, Jiaguo Zhou, Jun Lu, Xuefeng Lin
article en

Abstract

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.

Nature Communications
Sun Yat-sen University (CN), Cardiovascular Institute of the South (US), Nanfang Hospital (CN), The First Affiliated Hospital, Sun Yat-sen University (CN), Guangdong Academy of Medical Sciences (CN), Guangdong Provincial People's Hospital (CN), Southern Medical University (CN), Stanford University (US)
Openalex Percentile: Top 24%
Aortic aneurysm repair treatments
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