NOX4, a key NADPH oxidase enzyme generating reactive oxygen species, drives the development of abdominal aortic aneurysms (AAA) through cell-specific mechanisms involving extracellular matrix remodeling. Single-cell analysis of human AAA tissue revealed NOX4 expression primarily in fibroblasts, smooth muscle cells, and endothelial cells, with strong associations to ECM synthesis pathways. Knockout mice lacking Nox4 showed protection against experimental AAA formation. The research reveals a concerning cellular transformation process where lymphatic endothelial cells convert into myofibroblasts—a change linked to increased NOX4 expression and tissue remodeling that weakens vessel walls. This finding connects oxidative stress directly to the structural deterioration that makes aortic aneurysms prone to rupture. The study also identified disrupted blood vessel architecture in the vessel wall itself, with fewer small vessels and more large ones as aneurysms progress. While this preprint awaits peer review and results may change, it represents significant progress in understanding AAA pathogenesis. The cell-specific role of NOX4 could inform targeted therapies for this life-threatening condition, which currently has limited treatment options beyond surgical intervention.