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

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. Overall design: Splenic CD4+ T cells from iWT (WT) and Dlst-Treg iKO (KO) mice were cultured in Treg polarization condition for 2 days in the presence of 4-hydroxytamoxifen. Sorted iTregs (CD4+FoxP3-GFP+tdTomato-RFP+) were subjected to RNA sequencing.