IGF2BP2 regulates inflammation in ulcerative colitis through N6-methyladenosine-dependent modulation of CBR1.

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.