Metabolic reprogramming of pathogenic CD4⁺ T helper cells attenuates inflammatory bowel disease in mice.

Authors

Shravan K Mishra, Leena M Abdelrahman, Hyun Se Kim Lee, Lucía Valenzuela-Pérez, Dina F Manna, Tanner J Abram, Lama Mohamed Ali, Heidi M Davidson, Omar M Hassan, William A Faubion, Petra Hirsova, Adebowale O Bamidele

Published in

Science signaling. Volume 19. Issue 958. Pages eaeb2392. Oct 06, 2026. Epub Oct 06, 2026.

Abstract

CD4⁺ effector T helper 1 (T_H1) cells drive inflammatory bowel disease (IBD). Here, we investigated how integrated signaling, metabolic, and epigenetic programs sustain their pathogenic persistence. We found that enforcing mitochondrial pyruvate metabolism with methyl pyruvate (MePyr) suppressed T_H1 cell effector function and induced the acquisition of a regulatory-like phenotype. MePyr suppressed the activity of glycogen synthase kinase 3β (GSK3β), promoting a metabolic shift from glycolysis toward oxidative phosphorylation (OXPHOS) and limiting the accumulation of intracellular acetyl-CoA. This metabolic reprogramming decreased histone H3 acetylation at genes encoding inflammatory cytokines, thereby decreasing T_H1 cell-associated gene expression. Restoration of inflammatory cytokine production by acetate supplementation or histone deacetylase inhibition established acetyl-CoA-dependent histone acetylation as a mechanistic link between metabolic flux and effector function. Conversely, the cytokine interleukin-21 enhanced T_H1 cell effector activity by promoting a GSK3β-dependent shift from OXPHOS to glycolysis. Single-cell transcriptomic analysis of Crohn's disease tissue revealed enrichment of glycolytic gene programs in nonregulatory CD4⁺ T cells. Consistent with these findings, pharmacologic inhibition of GSK3β attenuated disease severity in a T cell-transfer mouse model of colitis. Together, these findings identify a GSK3β-dependent metabolic-epigenetic axis that sustains T_H1 cell pathogenicity and highlight GSK3β as a potential therapeutic target for IBD.

PMID:
42837442
Bibliographic data and abstract were imported from PubMed on 07 Oct 2026.

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