Targeting PCSK9 in Vascular Smooth Muscle Cells: An Effective Strategy to Suppress Ferroptosis and Attenuate Abdominal Aortic Aneurysm Progression

Abdominal aortic aneurysm (AAA) lacks effective pharmacotherapy. This study examines whether proprotein convertase subtilisin/kexin type 9 (PCSK9) drives ferroptosis in vascular smooth muscle cells (VSMCs) and whether its pharmacological degradation mitigates disease progression. PCSK9 is enriched in VSMCs of human AAA and in murine models induced by PPE or Ang II. SMC‐specific PCSK9 overexpression ( PCSK9 SMC OE ) increases aortic diameter, aggravates elastin fragmentation and collagen deposition and elevates MMP2/9 expression. Within aortic lesions, PCSK9 SMC OE enhances iron accumulation and lipid peroxidation while reducing glutathione GPX4, consistent with ferroptosis. In primary VSMCs, PCSK9 overexpression suppresses GPX4 and glutathione, increases malondialdehyde and Fe 2+ levels and impairs viability, whereas PCSK9 knockdown attenuates Ang II–induced ferroptosis. Mechanistically, PCSK9 triggers ferritinophagy, as shown by decreased ferritin heavy chain‐1 (FTH1) and nuclear receptor coactivator‐4 (NCOA4), an increased LC3‐II/I ratio and enhanced FTH1–LAMP1 colocalisation. Autophagy inhibition with bafilomycin A1 blocks Fe 2+ accumulation and rescues ferroptotic indices. The cell‐permeable peptide Cadd4 promotes PCSK9 degradation, restores FTH1 and NCOA4 and suppresses ferroptosis in VSMCs. In PPE and Ang II models, Cadd4 reduces aortic dilation, preserves medial structure and normalises ferroptosis and ferritinophagy markers. PCSK9 drives ferritinophagy‐dependent ferroptosis in VSMCs, and Cadd4 represents a promising therapeutic strategy for AAA.