Roxadustat Ameliorates Thoracic Aortic Dissection by Activating HIF‐1α‐Mediated Mitophagy to Inhibit Ferroptosis

Thoracic aortic dissection (TAD) is a life-threatening cardiovascular disease with limited pharmacological treatments. Vascular smooth muscle cell (VSMC) loss is a critical pathological feature of TAD. Roxadustat (ROX), a HIF stabilizer for renal anemia, was evaluated in a β-aminopropionitrile (BAPN)-induced TAD mouse model. It significantly improved survival, attenuated weight loss and aortic dilation, decreased the incidence of TAD, alleviated elastic fibers damage, and ultimately inhibited TAD progression. Mechanistically, ROX upregulated HIF-1α expression, reduced vascular wall iron deposition and lipid peroxidation products (MDA, 4-HNE), and normalized aberrant expression of ferroptosis markers ACSL4, TFR1, GPX4 and FTH1. In vitro, it mitigated Erastin/Ang II-induced VSMC ferroptosis, improved mitochondrial structure and function by enhancing oxygen consumption rate (OCR), restoring membrane potential, reducing reactive oxygen species (ROS), and boosting mitophagy via upregulating HIF-1α and mitophagy markers (PINK1, Parkin). The HIF-1α inhibitor KC7F2 and siHIF-1α reversed these effects. Taken together, our findings demonstrate that ROX protects against TAD by promoting HIF-1α expression to enhance mitophagy and inhibit VSMC ferroptosis, offering potential clinical implications for TAD prevention and treatment.