Downregulation of METTL3 enhances TRADD-mediated apoptosis in inflammatory bowel disease

Dysregulation of RNA N⁶-methyladenosine (m⁶A) modification in intestinal epithelial cells (IECs) compromises intestinal homeostasis, which is critical for maintaining gastrointestinal functions, immunity, and barrier integrity in inflammatory bowel disease (IBD). Here we explored the role of m⁶A modification, particularly through methyltransferase like 3 (METTL3), in IBD pathology and the apoptosis of intestinal stem cells (ISCs). Reduced m⁶A RNA methylation and METTL3 expression were detected in IBD tissues, which correlated with increased ISC apoptosis and spontaneous enteritis in METTL3-deficient models; mechanistically, Mettl3 depletion increased TRADD expression in a m⁶A-dependent manner, thereby augmenting the TNF-induced apoptosis pathway, whereas pharmacological inhibition of TRADD ameliorated the apoptotic phenotype in METTL3-deficient models and improved survival rates in the enteritis mouse model, suggesting a novel therapeutic avenue for IBD management. Collectively, METTL3-mediated m⁶A RNA methylation plays a pivotal role in maintaining intestinal homeostasis and is activated in ISCs to mitigate the hyperactivity of endogenous inflammatory signals; by modulating TRADD transcript metabolism, METTL3 limits excessive ISC apoptosis, providing insights into IBD pathogenesis and treatment strategies.