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Succinate drives gut inflammation by promoting FoxP3 degradation through a molecular switch

GSE277632 Mus musculus Expression profiling by high throughput sequencing 6 samples Submitted 2025/04/11 Platform GPL21103
Summary
Succinate levels are elevated in inflammatory bowel disease (IBD), but its role in disease pathogenicity remains unknown. This study shows that succinate promotes colitis in mice by reducing FoxP3 expression in regulatory T cells (Tregs) and increasing IL-17. Succinate selectively reduced the expression of 2-oxoglutarate dehydrogenase complex (OGDHc), the enzyme for succinyl-CoA synthesis, which in turn reduced FoxP3 succinylation and made FoxP3 lysine residues available for ubiquitination and Foxp3 protein degradation. Genetic deletion of Dlst, a member of OGDHc, in Tregs led to reduced FoxP3, impaired Treg function, and severe gut inflammation. Restoring FoxP3 fully rescued Dlst-deficient Treg immune suppressive functions. In IBD patients, FoxP3 and OGDHc levels were reduced in Tregs and negatively correlated with succinate levels and inflammation severity. This study identifies succinate as a pathogenic factor in IBD, uncovering a succinate-driven molecular switch that regulates FoxP3 stability and Treg function during inflammation.
Published in
Succinate drives gut inflammation by promoting FOXP3 degradation through a molecular switch
Wang H, Hu D, Cheng Y et al. · Nature immunology 2025 · PMID 40457062 · doi:10.1038/s41590-025-02166-y
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Also filed as BioProject PRJNA1163010 and SRA study SRP533746. Searching any of these in the dataset finder brings you back here.

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