DNMT3B attenuates the development of thoracic aortic aneurysm and dissection by suppressing TFEB-mediated autophagy in vascular smooth muscle cells.

While emerging evidence highlights the importance of DNA methyltransferase 3B (DNMT3B) in cardiovascular pathophysiology, its precise role in thoracic aortic aneurysm and dissection (TAAD) remains poorly understood. Here, we elucidate the function and underlying mechanisms of DNMT3B in TAAD pathogenesis. We found that DNMT3B expression was markedly downregulated in vascular smooth muscle cells (VSMCs) of both human and mouse TAAD tissues compared to healthy controls. In vivo, targeted overexpression of DNMT3B in VSMCs via adeno-associated virus delivery significantly decreased TAAD incidence, reduced aortic rupture rates, and attenuated aortic dilation. Conversely, VSMC-specific DNMT3B knockdown exacerbated disease progression. In vitro experiments, utilizing adenovirus-mediated overexpression and the inhibitor Nanaomycin A revealed that DNMT3B inhibits both VSMC autophagy and phenotypic switching. Mechanistically, DNMT3B prevents the maladaptive transition of VSMCs toward a synthetic phenotype through the transcriptional repression of transcription factor EB (TFEB), thereby curbing excessive autophagy. Collectively, our findings demonstrate a protective role for DNMT3B against TAAD, highlighting its function in preserving VSMC homeostasis via the transcriptional inhibition of TFEB.