<p>Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease associated with high mortality rates upon rupture. Guanylate binding protein 5 (GBP5) has been implicated in the exacerbation of inflammatory responses in various diseases, including rosacea, osteoarthritis, and lupus nephritis. However, its role in the development and progression of AAA remains unclear. This study aimed to investigate the role of GBP5 in the development and progression of AAA. An angiotensin II (Ang II)-infused ApoE^−/− mice, LPS-treated Raw 264.7 cells, and a Raw 264.7 and vascular smooth muscle cells (VSMCs) co-culture system were used to investigate the role of GBP5 in AAA progression. The effects of GBP5 knockdown on AAA were determined using histological assessments, immunohistochemistry, immunofluorescence, western blot, ELISA, and RT-qPCR experiments. GBP5 expression was upregulated in the aorta of Ang II-treated mice. Knockdown of GBP5 attenuated AAA progression, as evidenced by the reduced aortic diameter and preserved elastin integrity. GBP5 knockdown reduced inflammation and suppressed VSMC phenotypic switching in Ang II-induced mice. Mechanistically, GBP5 knockdown reversed Ang II-induced upregulation of TLR4 and p-NF-κB p65 levels in mouse aortas. In vitro, GBP5 silencing attenuated LPS-induced M1 macrophage polarization by modulating the TLR4/NF-κB pathway. Furthermore, GBP5 knockdown in macrophages inhibited VSMC phenotypic switching in the co-culture system. Our results demonstrated that GBP5 knockdown attenuated AAA progression by reducing reduced inflammation and inhibiting phenotypic switching of VSMCs through inactivation of the TLR4/NF-κB pathway. These results indicated that targeting GBP5 may be a potential therapeutic approach for AAA.</p>