Abdominal aortic aneurysm progression is driven by histone lactylation-mediated GLI3 activation

Abdominal aortic aneurysm (AAA) progression is closely linked to M1 macrophage polarization, yet the regulatory role of histone lactylation remains unclear. Combining clinical samples, animal models, and in vitro assays, we found that lactate-induced H3K18 lactylation (H3K18la) promotes M1 polarization (upregulating CD80/MCP-1/iNOS, downregulating CD206) in AAA. Multi-omics analysis revealed 305 dysregulated genes and 839 altered lactylation peaks in lactate-treated macrophages, with GLI3 emerging as a critical lactylation target. Knockdown of GLI3 suppressed M1 polarization, while lactate-enhanced GLI3 expression drove this process. Additionally, lactate-polarized M1 macrophages secreted exosomal SERPINE1, exacerbating endothelial dysfunction, a key mechanism in AAA pathogenesis. Our study uncovers a histone lactylation-GLI3 axis that orchestrates M1 polarization and exosome-mediated endothelial injury, offering new insights into AAA progression.