The STING inhibitor C-176 attenuates abdominal aortic aneurysm progression by suppressing macrophage inflammation

Abdominal aortic aneurysm (AAA) is a vascular condition characterized by chronic inflammation. The stimulator of interferon genes (STING) pathway is known to contribute to various inflammatory diseases; however, its specific role in AAA pathogenesis remains unclear. This study aims to investigate whether STING signaling participates in the inflammatory mechanisms driving AAA formation. AAA was induced in C57BL/6 male mice fed a high-fat diet via continuous angiotensin II (AngII) infusion using osmotic pumps. The mice were assigned to three groups: Control (saline), AngII + (AAA induction), and AngII + C-176 + (AngII plus daily administration of the STING inhibitor C-176). After 28 days, aortic tissues were collected and analyzed. Treatment with C-176 significantly alleviated AAA pathology, as evidenced by reduced aneurysm incidence, limited aortic dilation, and preserved elastic fiber structure. Although mortality showed a numerical decrease in the treatment group, this difference did not reach statistical significance. Moreover, C-176 downregulated the expression of STING, p-STING, p-TBK-1, and p-IRF-3 in aortic tissues compared to the AngII + group. It also markedly decreased macrophage infiltration and lowered the M1/M2 macrophage ratio. Immunofluorescence analysis confirmed STING colocalization with M1 macrophages within AAA lesions. The cGAS-STING signaling pathway contributes to AAA pathogenesis, partly by promoting pro-inflammatory M1 macrophage polarization.