Wu Weiyun, Zhou Zhuliang, Pang Cheng, Wen Xiaoyuan, Ye Shicai, Quan Juan-Hua, Li Heng, He Huanjin, Wu Bin, Tan Wenkai
Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Laboratory of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
Int Immunopharmacol. 2025 Aug 28;161:115072. doi: 10.1016/j.intimp.2025.115072. Epub 2025 Jun 16.
Ulcerative colitis (UC) is a chronic inflammatory disease characterized by damage to the colonic mucosa. N6-methyladenosine (m6A), an epigenetic modification of RNA, is involved in the pathogenesis of various human diseases. However, the function of m6A reader insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) in UC remains elusive. Herein, we performed bioinformatic analysis to find that IGF2BP2 expression is decreased in UC tissues, and IGF2BP2 downregulation is associated with disease severity. Furthermore, TNF-α inhibitors infliximab or golimumab treatment significantly increased IGF2BP2 expression in patients with UC, thereby indicating that IGF2BP2 may serve as a predictive biomarker for anti-TNF therapy selection. Knockdown of IGF2BP2 significantly activated the PI3K/Akt/NF-κB signaling pathway and exacerbated inflammation in tumor necrosis factor-α-stimulated Caco-2 cells and in mice with dextran sulfate sodium-induced colitis. Mechanistic studies showed that IGF2BP2 silencing decreased the stability of its target, carbonyl reductase 1 (CBR1) mRNA, in an m6A-dependent manner, thereby activating PI3K/Akt/NF-κB signaling. Moreover, CBR1 overexpression counteracted the proinflammatory effect of IGF2BP2 knockdown. Collectively, our findings demonstrate that IGF2BP2 is a crucial factor in UC, which exerts its effects through CBR1 and may represent a potential therapeutic target.
溃疡性结肠炎（UC）是一种以结肠黏膜损伤为特征的慢性炎症性疾病。N6-甲基腺苷（m6A）是一种RNA的表观遗传修饰，参与多种人类疾病的发病机制。然而，m6A阅读蛋白胰岛素样生长因子2 mRNA结合蛋白2（IGF2BP2）在UC中的功能仍不清楚。在此，我们进行了生物信息学分析，发现IGF2BP2在UC组织中的表达降低，且IGF2BP2下调与疾病严重程度相关。此外，肿瘤坏死因子-α抑制剂英夫利昔单抗或戈利木单抗治疗显著增加了UC患者的IGF2BP2表达，从而表明IGF2BP2可能作为抗TNF治疗选择的预测生物标志物。敲低IGF2BP2显著激活了PI3K/Akt/NF-κB信号通路，并加剧了肿瘤坏死因子-α刺激的Caco-2细胞和葡聚糖硫酸钠诱导的结肠炎小鼠的炎症。机制研究表明，IGF2BP2沉默以m6A依赖的方式降低了其靶标羰基还原酶1（CBR1）mRNA的稳定性，从而激活PI3K/Akt/NF-κB信号。此外，CBR1过表达抵消了IGF2BP2敲低的促炎作用。总的来说，我们的研究结果表明IGF2BP2是UC中的一个关键因素，它通过CBR1发挥作用，可能是一个潜在的治疗靶点。
