1,2,3,6-Tetragalloylglucose inhibits hnRNPA2B1/TRAIL Axis to attenuate apoptosis and barrier dysfunction in intestinal epithelial cells: A potential therapeutic avenue for IBD.

Intestinal epithelial cells (IECs) injury and intestinal barrier function impairment are key risk factors for the pathogenesis and progression of inflammatory bowel disease (IBD). Heterogeneous nuclear ribonucleoprotein A2B1 (A2B1), as an N6-methyladenosine (m6A)-binding protein, is upregulated in intestinal epithelial cells of IBD patients. However, the role of m6A modifications and A2B1 in intestinal epithelial cell damage and intestinal barrier dysfunction remains largely unexplored. This study confirmed that A2B1 was significantly upregulated in IECs and tissues in IBD. Elevated expression of A2B1 was also found in tumor necrosis factor alpha (TNF-α) induced Caco-2 cells, intestinal organoids and dextran sulfate sodium (DSS) induced mouse model colon tissues. Overexpression of A2B1 in IECs led to increased apoptosis and barrier dysfunction, while knockdown of A2B1 ameliorated these effects. A2B1 interacted with TNF-related apoptosis inducing ligand (TRAIL) in an m6A dependent manner and regulated intestinal epithelial cell apoptosis and barrier function by modulating TRAIL expression. 1,2,3,6-Tetragalloylglucose (TeGG) was identified as a potent inhibitor of A2B1, effectively blocking TNF-α induced TRAIL upregulation and barrier damage in both cellular and organoid models. The study results suggest that A2B1 plays a crucial role in IBD by modulating TRAIL mRNA, leading to IECs apoptosis and intestinal barrier dysfunction. Targeting the A2B1-TRAIL interaction with small-molecule inhibitors like TeGG offers a novel and promising therapeutic approach for the treatment of IBD.