m6A demethylase FTO promotes the progression of abdominal aortic aneurysm through PDK4-mediated apoptosis

N6-methyladenosine (m6A) is one of the most abundant forms of methylation modification in mRNA, regulating different stages of mRNA metabolism, including folding, maturation, output, translation, and decay. However, the effect of m6A modification and m6A demethylase fat mass and obesity associated (FTO) on abdominal aortic aneurysms remains unclear. We found that FTO expression levels were elevated in both internal and external models of abdominal aorta, and silencing FTO could partially reverse AngII-induced apoptosis of VSMCs. Combined RNA-seq and MeRIP-seq analysis further identified pyruvate dehydrogenase kinase 4 (PDK4) as the target gene of FTO-mediated m6A modification. FTO mediates m6A demethylation in the 3' Untranslated Regions region of PDK4 mRNA and induces its degradation through a YTH N6-Methyladenosine RNA Binding Protein F2-dependent mechanism. Overexpression of PDK4, a key enzyme in mitochondrial glucose metabolism and a novel regulator of mitochondria-associated endoplasmic reticulum integrity, reversed apoptosis inhibition after FTO silences. The results suggest that FTO regulates vascular smooth muscle cell apoptosis by mediating m6A demethylation of PDK4 mRNA and promoting its degradation, dependent on the YTHDF2 mechanism. However, PDK4 overexpression reverses the apoptosis inhibitory effect after FTO silencing.