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

Abstract

Dysregulation of RNA N-methyladenosine (mA) 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 mA modification, particularly through methyltransferase like 3 (METTL3), in IBD pathology and the apoptosis of intestinal stem cells (ISCs). Reduced mA 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 mA-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 mA 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.