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<p>Succinate levels are increased in inflammatory bowel disease (IBD), but its role in disease pathogenicity remains unknown. Here we showed that succinate promoted colitis in mice by reducing the expression of FOXP3 and increasing the expression of interleukin-17 in regulatory T (T<sub>reg</sub>) cells. 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 <i>Dlst</i>, a member of OGDHc, in T<sub>reg</sub> cells led to reduced expression of FOXP3, impaired T<sub>reg</sub> cells function and severe gut inflammation. Restoring FOXP3 expression fully rescued the immune suppressive functions of <i>Dlst</i>-deficient T<sub>reg</sub> cells. In individuals with IBD, FOXP3 and OGDHc levels were reduced in T<sub>reg</sub> cells 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 T<sub>reg</sub> cells function during inflammation.</p>

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Succinate drives gut inflammation by promoting FOXP3 degradation through a molecular switch

  • 期刊论文

  • 发表日期：

    2025年6月2日

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  • Hai Wang,
  • Danqing Hu,
  • Yang Cheng,
  • Qiong Gao,
  • Kun Liu,
  • Nikita L. Mani,
  • Amy Y. Tang,
  • Radhika Iyer,
  • Beixue Gao,
  • Leyu Sun,
  • Qi Zhou,
  • Qin Yu,
  • Samuel E. Weinberg,
  • Xiaoyu Zhang,
  • Yingzi Cong,
  • Parambir S. Dulai,
  • Yana Zhang,
  • Zheng Liu,
  • Deyu Fang

摘要

Succinate levels are increased in inflammatory bowel disease (IBD), but its role in disease pathogenicity remains unknown. Here we showed that succinate promoted colitis in mice by reducing the expression of FOXP3 and increasing the expression of interleukin-17 in regulatory T (Treg) cells. 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 Treg cells led to reduced expression of FOXP3, impaired Treg cells function and severe gut inflammation. Restoring FOXP3 expression fully rescued the immune suppressive functions of Dlst-deficient Treg cells. In individuals with IBD, FOXP3 and OGDHc levels were reduced in Treg cells 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 cells function during inflammation.