m ⁶ A‐Mediated Glycolysis by IL‐37 Drives T Cell Metabolic Reprogramming to Regulate Colitis

ABSTRACT N6‐methyladenosine (m ⁶ A) modification and T‐cell metabolic reprogramming are increasingly recognized as critical drivers of inflammatory bowel disease (IBD). However, how the anti‐inflammatory cytokine interleukin‐37 intersects with m ⁶ A‐mediated metabolic regulation remains unclear. Here, we show that IL‐37 alleviates colitis by reducing global m ⁶ A levels and reshaping CD4 ⁺ T‐cell metabolism. Mechanistically, IL‐37 signals through its receptor SIGIRR to inhibit IRAK4 and JNK phosphorylation, suppress NF‐κB p65 activation, and downregulate METTL14, thereby decreasing m ⁶ A deposition. The IL‐37/METTL14 axis notably reduces m ⁶ A enrichment at the A2445 site in the 3′UTR of SLC2A1, destabilizing its mRNA and suppressing glycolysis. In vitro T‐cell polarization and adoptive transfer of METTL14‐overexpressing CD4 ⁺ T cells confirmed that this metabolic shift restrains Th1/Th17 differentiation while promoting Th2 expansion. Together, these findings reveal the IL‐37/SIGIRR–METTL14–m ⁶ A axis as a novel regulator of T‐cell metabolism and highlight SLC2A1 as a potential therapeutic target in IBD.