TRAF6 promotes abdominal aortic aneurysm development by activating macrophage pyroptosis via the NLRP3/Caspase1/GSDMD pathway

Abstract Abdominal aortic aneurysm represents a critical pathology of the aorta that currently lacks effective pharmacological interventions. TNF receptor‐associated factor 6 (TRAF6) has been established to be involved in cardiovascular diseases such as atherosclerosis, hypertension, and heart failure. However, its role in abdominal aortic aneurysm (AAA) remains unclear. This study aimed to explore the role of TRAF6 on AAA formation and its underlying mechanisms. Single‐cell RNA sequencing of human AAA tissues demonstrated that TRAF6 was significantly upregulated in aortic macrophages. Moreover, overexpression of TRAF6 promotes AAA formation in elastase‐induced C57BL/6 mice, while TRAF6 pharmacological inhibition could attenuate AAA development. Consistently, inhibition of TRAF6 in macrophages through in vitro methods notably limits their pyroptosis, while also diminishing proinflammatory responses in these cells. Mechanistically, TRAF6 can modulate macrophage pyroptosis through the NLRP3/Caspase1/GSDMD signaling pathway. Our study highlights the crucial role of the TRAF6/NLRP3/Caspase1/GSDMD axis in macrophage pyroptosis and AAA, offering potential biomarkers and therapeutic targets for AAA.