Kaempferol Suppresses Abdominal Aortic Aneurysm Development via Modulation of Macrophage Polarization Through the STAT/TNF Signaling Pathway

The global incidence of abdominal aortic aneurysm (AAA) is rising, posing a significant health threat. AAA rupture can lead to life-threatening internal bleeding, yet its underlying pathophysiological mechanisms remain incompletely understood. Furthermore, effective pharmacological interventions to slow or halt AAA progression remain elusive. This study investigates the potential of kaempferol (KA) as a preventive agent for AAA. Using a PPE-induced murine AAA model with preventive KA administration commencing on the day of surgery, we evaluated its effects on AAA formation. Further analysis in vivo and in vitro assessed KA's impact on macrophage polarization. Network pharmacology was employed to predict key targets, which were subsequently validated through molecular docking, cellular thermal shift assay (CETSA), and rescue experiments. Preventive KA administration significantly attenuated AAA formation, as evidenced by reduced aortic dilation, elastin degradation, and Collagen deposition. KA inhibited M1 macrophage polarization (reducing iNOS/CD86) and promoted M2 polarization (increasing Arg1/CD206). Network pharmacology predicted STAT3, STAT1, and TNF as key targets, which was confirmed by molecular docking and CETSA showing direct binding. Importantly, KA inhibited LPS-induced STAT3/STAT1 phosphorylation and TNF expression. Rescue experiments using specific agonists reversed KA's effects on macrophage polarization, demonstrating its action is mediated through the STAT/TNF signaling pathway. Our findings suggest that KA holds promise as a novel preventive strategy for AAA, with its mechanisms of action involving the regulation of macrophage polarization and the STAT/TNF signaling pathway.

Kaempferol; STAT1; STAT3; TNF‐α; abdominal aortic aneurysm; macrophage polarization.