Unveiling the role of STAT1-activated macrophages in abdominal aortic aneurysm: Insights from scRNA-seq and prognostic signature development

Abstract

Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disorder with no effective drug treatment. Inflammation and macrophage infiltration in the abdominal aorta play a pivotal role in AAA development, progression, and rupture. However, the precise molecular mechanisms driving these processes remain unclear. To address this, we analyzed single-cell RNA sequencing datasets from three AAA mouse models and two healthy controls. Our findings revealed that AAA samples showed a marked increase in macrophage populations, with a shift toward pro-inflammatory M1 polarization compared to the predominantly M2 phenotype in controls. CellChat analysis revealed that the STAT1 pathway may mediate the enhanced intercellular communication between M1 and M2 macrophages. SCENIC analysis further identified STAT1 as a central transcriptional regulator in macrophages. We also developed a ten-gene inflammatory signature predictive of AAA prognosis, validated with external datasets, and confirmed STAT1's involvement via Western blotting and real-time PCR. These findings highlight the importance of macrophage polarization and STAT1-driven signaling in AAA pathogenesis. The identified gene signature offers potential for risk stratification and therapeutic targeting, advancing both mechanistic understanding and clinical management of AAA.