m6A-Mediated Glycolysis by IL-37 Drives T Cell Metabolic Reprogramming to Regulate Colitis

Xiaoyan Wang; Jiadong Yu; Guolin Li; Ya Li; Fanlian Zeng; Jing Hu; Yifan Zhou; Chengcheng Yue; Qixiang Zhao; Chen Zhang; Hong Zhou; Fulei Zhao; Yawen Hu; Pei Zhou; Linna Gu; Yuting Feng; Mingxiang He; Shishi Huang; Xiaochi Sun; Xinmeng Wang; Jie Tang; Xinyu Zeng; Wenling Wu; Nongyu Huang; Xinai Cui; Kaijun Cui; Jiong Li

doi:10.1002/advs.202520472

m⁶A-Mediated Glycolysis by IL-37 Drives T Cell Metabolic Reprogramming to Regulate Colitis

Adv Sci (Weinh). 2026 Jun 9:e20472. doi: 10.1002/advs.202520472. Online ahead of print.

Authors

Xiaoyan Wang¹, Jiadong Yu¹, Guolin Li¹, Ya Li¹, Fanlian Zeng¹, Jing Hu¹, Yifan Zhou¹, Chengcheng Yue¹, Qixiang Zhao¹, Chen Zhang¹, Hong Zhou¹, Fulei Zhao¹, Yawen Hu¹, Pei Zhou¹, Linna Gu¹, Yuting Feng¹, Mingxiang He¹, Shishi Huang¹, Xiaochi Sun², Xinmeng Wang², Jie Tang¹, Xinyu Zeng¹, Wenling Wu¹, Nongyu Huang¹, Xinai Cui³, Kaijun Cui², Jiong Li¹

Affiliations

¹ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China.
² Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
³ CDUTCM-KEELE Joint Health and Medical Sciences Institute, Chengdu University of Traditional Chinese Medicine, Chengdu, China.

Abstract

N6-methyladenosine (m⁶A) 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 m⁶A-mediated metabolic regulation remains unclear. Here, we show that IL-37 alleviates colitis by reducing global m⁶A 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 m⁶A deposition. The IL-37/METTL14 axis notably reduces m⁶A 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-m⁶A axis as a novel regulator of T-cell metabolism and highlight SLC2A1 as a potential therapeutic target in IBD.

Keywords: IL‐37; T cell metabolism; colitis; glycolysis; m6A methylation.

Abstract

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