NCOA4 Accelerates Abdominal Aortic Aneurysm Formation by Regulating Macrophage Activation and Ferroptosis via STAT1–CH25H Axis

Abdominal aortic aneurysm (AAA) is a life-threatening condition lacking effective pharmacological treatments, with emerging evidence highlighting the fundamental role of ferroptosis in its progression. Nuclear receptor coactivator 4 (NCOA4), known to mediate ferritinophagy and contribute to ferroptosis, is upregulated in macrophages from both angiotensin II (Ang II)-induced murine AAA models and human AAA tissues. Global deletion of Ncoa4 in mice suppressed Ang II-induced AAA formation. Combined approaches using bone marrow transplantation and macrophage-specific adeno-associated virus (AAV) confirmed that Ncoa4 knockdown in macrophages alleviates extracellular matrix (ECM) degeneration, inflammation, and vascular damage. Mechanistically, NCOA4 interacts with signal transducer and activator of transcription 1 (STAT1) to co-activate the transcription of cholesterol 25-hydroxylase (CH25H), an enzyme that catalyzes the production of 25-hydroxycholesterol (25-HC). Elevated 25-HC levels were detected in the serum of both Ang II-induced AAA mice and human AAA patients, and they promoted macrophage activation and ferroptosis, thereby driving AAA progression. Importantly, knockdown of Ch25h using lipid nanoparticle-loaded microbubbles (LNP/MBs) attenuated macrophage ferroptosis and AAA progression. These findings reveal a critical role of the NCOA4/STAT1/CH25H axis in AAA pathogenesis and offer promising biomarkers and therapeutic strategies for the disease.