BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by sustained epithelial damage and heightened immune activation, with intestinal epithelial cells playing a pivotal role in its pathogenesis. N6-methyladenosine (m6A) methylation, a prevalent RNA epigenetic modification, has garnered increasing attention for its potential involvement in UC progression. However, the precise role of m6A in intestinal epithelial cells during UC remains unclear. PURPOSE: This study investigated the role of the m6A reader protein IGF2BP2 in intestinal epithelial cells within the context of UC pathogenesis. Additionally, the mechanistic contributions of IGF2BP2 were explored through human tissue samples, UC cell models, and animal models. METHODS: m6A-related genes differentially expressed in intestinal epithelial cells of patients with UC were identified via analysis of single-cell sequencing data from public databases. These findings were validated using data from our research group and transcriptomic datasets. IGF2BP2 expression was confirmed at the human tissue and UC cell model levels through IHC, Western blot, IF, and RT-qPCR. Lentivirus-mediated knockdown and overexpression of IGF2BP2 were performed, followed by transcriptomic sequencing to identify downstream targets and signaling pathways using the starBase and SRAMP databases. To elucidate the m6A-dependent regulatory mechanism of IGF2BP2, functional assays, including meRIP-qPCR, RNA pulldown, RIP, mRNA stability assays, and m6A inhibitor treatments, were conducted. Lastly, DSS-induced UC mouse models, including IGF2BP2 knockout mice and AAV9-mediated LGI4 overexpression rescue experiments, were utilized to validate findings through histological analysis, body weight measurements, disease activity index (DAI) scoring, and molecular assessments. RESULTS: Bioinformatics and single-cell sequencing analyses revealed a marked downregulation of IGF2BP2 in intestinal epithelial cells of patients with UC. This reduction was further confirmed in human tissue and UC cell models, correlating with increased levels of inflammatory markers IL-1beta, COX-2, and IL-18. Transcriptomic and functional studies indicated that IGF2BP2 stabilizes LGI4 mRNA, thereby inhibiting the MEK1/2-ERK1/2 signaling pathway and suppressing pro-inflammatory cytokine expression. In vivo, IGF2BP2 expression was significantly reduced in DSS-induced UC mice, with concomitant upregulation of IL-1beta, COX-2, and IL-18. IGF2BP2 knockout exacerbated UC severity, led to LGI4 downregulation, and caused hyperactivation of the MEK1/2-ERK1/2 pathway. Conversely, AAV9-mediated LGI4 overexpression partially rescued these effects. CONCLUSION: These results suggest that IGF2BP2 stabilizes LGI4 mRNA in an m6A-dependent manner, inhibiting the MEK1/2-ERK1/2 pathway and inflammation in intestinal epithelial cells, ultimately mitigating UC progression. The IGF2BP2-LGI4 axis represents a promising therapeutic target for UC prevention and treatment.