Macrophage Gsα promotes NLRP3 stability and its intervention attenuates abdominal aortic aneurysm in male mice.

Abdominal aortic aneurysm (AAA) is a life-threatening degenerative aortic disease that primarily affects older individuals. While macrophages are central to AAA pathogenesis, the regulatory role of the stimulatory G protein α subunit (Gsα) in macrophages remains poorly understood. In this study, using an Angiotensin Ⅱ-induced abdominal aortic aneurysm model on male mice, we demonstrate that macrophage-specific Gnas deficiency significantly attenuates AAA progression. Mechanistically, Gsα directly interacts with NLRP3 to promote inflammasome activation. Further cellular investigations indicate that Gsα maintains NLRP3 stability by sterically hindering its association with the E3 ubiquitin ligase BTRC, thereby preventing NLRP3 ubiquitination and subsequent degradation. Furthermore, lipid nanoparticles (LNPs)-mediated delivery of Gsα siRNA to monocytes/macrophages effectively suppresses NLRP3 expression and markedly reduces AAA progression in vivo. Our findings identify Gsα as a regulator in the activation of the NLRP3 inflammasome and provide a potential therapeutic target for AAA.