N6-methyladenosine (m⁶A) 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 m⁶A methylation, catalyzed by METTL3, promoted TXNIP translation via YTHDF1 binding to m⁶A 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 m⁶A-dependent regulatory program governing TXNIP expression and highlight therapeutic opportunities for targeting AAA progression.