# N6-methyladenosine (m6A) modification of TXNIP in 3′UTR instigates abdominal aorta aneurysm in mice

## TL;DR

This study shows how a specific RNA modification in the TXNIP gene contributes to the development of abdominal aortic aneurysms in mice.

## Contribution

The paper reveals a novel m6A-dependent regulatory mechanism controlling TXNIP expression in vascular smooth muscle cells during aneurysm progression.

## Key findings

- TXNIP upregulation in vascular smooth muscle cells drives abdominal aortic aneurysm formation.
- m6A modification in the TXNIP 3′UTR promotes cap-independent translation via YTHDF1 binding.
- YTHDF2 downregulation stabilizes TXNIP mRNA in aneurysm conditions.

## Abstract

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−/−TXNIPSM−/−) 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.

•TXNIP upregulation induces AAA formation•Silencing YTHDF2 increased TXNIP mRNA stability•TXNIP translation is YTHDF1-binding dependent•m6A within 3′UTR of TXNIP mRNA promotes its cap-independent translation

TXNIP upregulation induces AAA formation

Silencing YTHDF2 increased TXNIP mRNA stability

TXNIP translation is YTHDF1-binding dependent

m6A within 3′UTR of TXNIP mRNA promotes its cap-independent translation

Biochemistry; Molecular biology