METTL14 promotes ferroptosis in smooth muscle cells during thoracic aortic aneurysm by stabilizing the m⁶A modification of ACSL4

Thoracic aortic aneurysm (TAA) is a vascular disease associated with high mortality rates. Ferroptosis has been shown to mediate the transformation of vascular smooth muscle cells (VSMCs). However, the regulatory mechanisms by which ferroptosis influences TAA remain unclear. In this study, we induced TAA mouse models using angiotensin II (Ang II) and evaluated the impact of ferroptosis on the pathological changes observed in TAA mice, employing liproxstatin-1 as a treatment. In addition, we assessed the regulatory effect of METTL14 on the ferroptosis of VSMCs after treating them with a ferroptosis activator (imidazole ketone erastin, IKE). RNA binding protein immunoprecipitation (RIP) and RNA pull-down assays were conducted to investigate the interaction between acyl-CoA synthase long-chain family member 4 (ACSL4) mRNA and the proteins METTL14 or IGF2BP2. The results indicated that the level of ferroptosis was elevated in the thoracic aorta of TAA mice, and METTL14 was upregulated in TAA models and IKE-induced VSMCs. Knockdown of METTL14 was found to inhibit the progression of TAA by reducing the ferroptosis of VSMCs. Furthermore, IGF2BP2 recognized METTL14-modified ACSL4 mRNA and regulated its stability, thereby mediating the ferroptosis of VSMCs. Collectively, the effects of METTL14 on VSMC ferroptosis present therapeutic potential for the treatment of TAA.NEW & NOTEWORTHY Our study confirmed that METTL14 can induce ferroptosis in vascular smooth muscle cells during the progression of thoracic aortic aneurysm by mediating the m⁶A modification of ACSL4 mRNA.