N6-methyladenosine (m(6)A) modification of TXNIP in 3'UTR instigates abdominal aorta aneurysm in mice.

The thioredoxin-interacting protein (TXNIP) pathway is a central regulator of oxidative stress and contributes to vascular pathology. Here, we define how stress-responsive mRNA methylation controls TXNIP expression and drives abdominal aortic aneurysm (AAA). In angiotensin II (AngII)-infused ApoE (-/-) mice, TXNIP was markedly elevated in vascular smooth muscle cells (VSMCs), as confirmed by histological, protein, and transcript analyses. VSMC-specific TXNIP deletion (ApoE (-/-) TXNIP (SM-/-) ) significantly reduced AAA incidence, aortic remodeling, and elastic fiber degradation, establishing its essential role in disease progression. Mechanistic studies revealed that elevated m(6)A methylation, catalyzed by METTL3, promoted TXNIP translation via YTHDF1 binding to m(6)A sites within the 3' untranslated region (UTR), whereas YTHDF2 downregulation in AAA stabilized TXNIP transcripts. TXNIP translation also proceeded through a cap-independent process enhanced by mTOR inhibition. These findings identify an integrated m(6)A-dependent regulatory program governing TXNIP expression and highlight therapeutic opportunities for targeting AAA progression.