Ferrostatin‐1 inhibits ferroptosis of vascular smooth muscle cells and alleviates abdominal aortic aneurysm formation through activating the SLC7A11/GPX4 axis

Ferroptosis, a type of iron‐catalyzed necrosis, is responsible for vascular smooth muscle cell (VSMC) death and serves as a potential therapeutic target for alleviating aortic aneurysm. Here, our study explored the underlying mechanism of ferroptosis affecting VSMC functions and the resultant formation of AAA using its inhibitor Ferrostatin‐1 (Fer‐1). Microarray‐based gene expression profiling was employed to identify differentially expressed genes related to AAA and ferroptosis. An AAA model was established by angiotensin II (Ang II) induction in apolipoprotein E‐knockout (ApoE−/−) mice, followed by injection of Fer‐1 and RSL‐3 (ferroptosis inducer). Then, the role of Fer‐1 and RSL‐3 in the ferroptosis of VSMCs and AAA formation was analyzed in Ang II‐induced mice. Primary mouse VSMCs were cultured in vitro and treated with Ang II, Fer‐1, sh‐SLC7A11, or sh‐GPX4 to assess the effect of Fer‐1 via the SLC7A11/GPX axis. Bioinformatics analysis revealed that GPX4 was involved in the fibrosis formation of AAA, and there was an interaction between SLC7A11 and GPX4. In vitro assays showed that Fer‐1 alleviated Ang II‐induced ferroptosis of VSMCs and retard the consequent AAA formation. The mechanism was associated with activation of the SLC7A11/GPX4 pathway. Silencing of SLC7A11 or GPX4 could inhibit the ameliorating effect of Fer‐1 on the ferroptosis of VSMCs. In vivo animal studies further demonstrated that Fer‐1 inhibited Ang II‐induced ferroptosis and vessel wall structural abnormalities in AAA mouse through activation of the SLC7A11/GPX4 pathway. Fer‐1 may prevent AAA formation through activation of the SLC7A11/GPX4 pathway. This study investigates Ferrostatin‐1's (Fer‐1) role in inhibiting ferroptosis in vascular smooth muscle cells (VSMCs), crucial for preventing abdominal aortic aneurysm (AAA). Employing an AAA model in ApoE−/− mice, Fer‐1's impact on VSMCs ferroptosis and AAA formation is explored, highlighting the SLC7A11/GPX4 pathway's activation as a key mechanism. The research demonstrates Fer‐1's potential in AAA treatment by modulating lipid peroxidation and structural abnormalities in vessel walls.