Targeting RUNX3 alleviates abdominal aortic aneurysm by ameliorating oxidative stress via mitophagy.

This study aims to investigate the role of RUNX3 in the pathogenesis and progression of abdominal aortic aneurysm (AAA). AAA is a critical vascular disease characterized by progressive dilation of the aortic wall, and as the aneurysm grows, the risk of rupture significantly increases, leading to sharply elevated mortality. Recent studies have indicated that mitochondrial dysfunction plays a key role in the pathological process of AAA. This study focuses on RUNX3 and explores whether it participates in AAA progression by regulating mitophagy. AAA was induced in male C57BL/6 mice by pancreatic elastase and calcium chloride. Aortic morphology and pathology were assessed by H&E and EVG staining. Oxidative stress was measured by MDA and SOD levels. RUNX3 and mitophagy-related proteins were analyzed by Western blot. AAV2/9-mediated RUNX3 knockdown in vascular smooth muscle cells was combined with Mdivi-1 (a mitochondrial fission inhibitor, used to suppress mitophagy) for rescue experiments. Mice in the AAA model group showed significant local dilation of the abdominal aorta. H&E and EVG staining revealed disorganized aortic wall structure and elastic fiber fragmentation, and tissue oxidative stress levels were elevated. Western blot analysis showed that RUNX3 expression was significantly higher in the AAA group than in the sham group, while mitophagy-related protein expression was decreased. AAV2/9-mediated knockdown of RUNX3 significantly ameliorated AAA-related pathological damage, promoted mitophagy, and reduced oxidative stress; however, combined application of Mdivi-1 reversed the protective effects conferred by RUNX3 knockdown. This study suggested that RUNX3 expression is upregulated during AAA development and may promote disease progression by inhibiting mitophagy and exacerbating oxidative stress. Targeting RUNX3 may represent a potential strategy for alleviating AAA.