美国西北大学范伯格医学院研究团队近日取得一项新成果。经过不懈努力，他们的研究报道了琥珀酸盐通过分子开关促进FOXP3降解，从而引发肠道炎症。相关论文于2025年6月2日发表在《自然—免疫学》杂志上。

在这里，研究人员发现琥珀酸盐通过降低FOXP3的表达和增加调节性T （T_reg）细胞中白细胞介素-17的表达来促进小鼠结肠炎。琥珀酸选择性地降低了合成琥珀酰辅酶a的2-氧戊二酸脱氢酶复合物（OGDHc）的表达，从而降低了FOXP3的琥珀酰化，使FOXP3赖氨酸残基可用于泛素化和FOXP3蛋白降解。T_reg细胞中OGDHc成员Dlst基因缺失导致FOXP3表达降低，T_reg细胞功能受损，严重的肠道炎症。恢复FOXP3表达完全恢复了Dlst缺陷T_reg细胞的免疫抑制功能。在IBD患者中，T_reg细胞中的FOXP3和OGDHc水平降低，并与琥珀酸水平和炎症严重程度呈负相关。本研究确定琥珀酸盐是IBD的致病因子，揭示了在炎症期间调节FOXP3稳定性和T_reg细胞功能的琥珀酸盐驱动的分子开关。

据介绍，琥珀酸盐水平在炎症性肠病（IBD）中升高，但其在疾病致病性中的作用尚不清楚。

附：英文原文

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

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

Issue&Volume: 2025-06-02

Abstract: 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.

DOI: 10.1038/s41590-025-02166-y

Source: https://www.nature.com/articles/s41590-025-02166-y