Abstract
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.
Data availability
Source data are provided for all experimental results presented in the main manuscript and the Supplementary Information. The data from Olink technology to detect a comprehensive cytokine panel are presented as Supplementary Data 1. Source data are provided with this paper.
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Acknowledgements
This study was supported by grants from the Taishan Scholar Project of Shandong Province of China (No. tstp20240852 to W.Z.), the Natural Science Foundation of Shandong Province (ZR2020QH024 to X.Q., ZR2024ZD23 to W.Z., ZR2021MH316 to X.D., ZR2025QC1648 to L.H.), the National Natural Science Foundation of China (No. 82000435 to X.Q., 82470499 and 82270457 to W.Z.), and the Postdoctoral Innovation Project of Shandong Province (SDCX-ZG-202400016) to L.H.
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L.H., X.Q., W.J., and W.Z. designed the study. L.H., X.Q., Q.R., and H.L. performed the experiments and analyzed the results. L.H. and W.Z. drafted the manuscript. M.C., L.S.W., J.Y., C.Z., X.D., W.J., and W.Z. revised the manuscript for important intellectual content. All authors have read and approved the final manuscript.
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Nature Communications thanks Hafid Ait-Oufella, Jianxiang Zhang, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
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He, L., Qin, X., Ren, Q. et al. Macrophage Gsα promotes NLRP3 stability and its intervention attenuates abdominal aortic aneurysm in male mice. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71198-1
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DOI: https://doi.org/10.1038/s41467-026-71198-1
