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

Abstract

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.