METTL3 suppresses pyroptosis in obstructive sleep apnea-associated hypertension via YTHDF2-mediated SOX4 mRNA...

Obstructive sleep apnea (OSA) is frequently complicated by hypertension, with approximately 60% of patients exhibiting both conditions. However, the epigenetic mechanisms underlying this comorbidity remain largely unexplored. N6-methyladenosine (m6A), the most abundant internal RNA modification, has emerged as a critical regulator of cardiovascular pathology, yet its role in OSA-associated hypertension (OSA-HTN) is unknown. Here, we investigated the contribution of m6A RNA methylation to OSA-HTN pathogenesis. In a chronic intermittent hypoxia (CIH) mouse model and hypoxia-stimulated aortic vascular smooth muscle cells (AVSMCs), we observed marked inflammatory injury, pyroptosis, and decreased expression of methyltransferase-like 3 (METTL3) along with global m6A levels. Overexpression of METTL3 significantly attenuated hypoxia-induced pyroptosis and inflammation by downregulating SRY-box transcription factor 4 (SOX4), a pro-inflammatory transcription factor. Mechanistically, CIH suppressed YTH N6-methyladenosine RNA-binding protein 2 (YTHDF2), an m6A reader that directly binds SOX4 mRNA, while METTL3-mediated m6A modification enhanced YTHDF2-dependent SOX4 mRNA degradation. Knockdown of YTHDF2 abolished the suppressive effect of METTL3 on SOX4 stability, confirming a METTL3-m6A-YTHDF2 regulatory axis. This METTL3-dependent regulation of YTHDF2-SOX4 interaction and SOX4 mRNA decay was also validated in mouse aortic endothelial cells. Furthermore, in vivo silencing of SOX4 alleviated CIH-induced pyroptosis and inflammation in cardiac and aortic tissues. Notably, pharmacological activation of METTL3 or METTL3 overexpression similarly attenuated CIH-induced cardiac and aortic tissue injury in OSA-HTN mice. In conclusion, our findings identify a novel METTL3-YTHDF2-SOX4 axis that governs hypoxia-induced pyroptosis and inflammation, providing new mechanistic insights into the epigenetic regulation of OSA-HTN and highlighting potential therapeutic targets.