Targeting GPX4 alleviates ferroptosis and retards abdominal aortic aneurysm formation

Abdominal aortic aneurysm (AAA) is a potentially fatal Cardiovascular Disease, closely related to inflammation and loss of vascular smooth muscle cells (VSMCs). Ferroptosis is an iron-dependent cell death associated with peroxidation of lipids. However, the direct role of Glutathione Peroxidase 4 (GPX4) itself determined Ferroptosis in the course of AAA pathogenesis remains unknown. Here, we reported that Ferroptosis was triggered in human AAA, elastase- and angiotensin II (Ang II)-induced mouse AAA, and Ang II-incubated VSMCs. Inhibition of Ferroptosis via global genetic overexpression of GPX4, a critical anti-ferroptosis molecule, markedly prevented both vascular remodeling and inflammatory response. Mechanistically, GPX4 changed the migration and activation of macrophages/monocytes in AAA tissues in mice. Experiments in vitro demonstrated that overexpression of GPX4 prevented the JAK1/STAT3 signaling activation in VSMCs induced by IL-6, production of pro-inflammatory macrophages. Finally, the role of Ferroptosis was confirmed on an Ang II-induced mice AAA model. These results emphasized the significance of Ferroptosis in AAA, and provided novel insights that therapy focusing on GPX4 might be a promising strategy for treatment of AAA in the clinic.