IGF2BP2 attenuates intestinal epithelial cell ferroptosis in colitis by stabilizing m6A-modified GPX4 mRNA

Background: Ulcerative colitis (UC) is a chronic and uncontrolled inflammatory bowel disease. N6-methyladenine (m6A) is a reversible mRNA modification method. IGF2BP2 is an RNA-binding protein regulated by m6A methylation. However, understanding of m6A-related proteins in UC is limited. This study was to analyze the function and related mechanism of IGF2BP2 in UC. Methods: The UC models were established by dextran sulfate sodium (DSS) in NCM460 cells and mice. The expression of IGF2BP2 and GPX4 in UC were detected by qPCR and western blot. The effects of IGF2BP2 on inflammation, ferroptosis and colon injury were measured by gain-and loss-of-function experiments. This study conducted a clinical evaluation of mice using the Disease Activity Index score. The molecular mechanism of IGF2BP2 in ferroptosis were analyzed by m6A RNA methylation quantification kit, RNA immunoprecipitation-qPCR analysis, and RNA stability assay. Results: IGF2BP2 and GPX4 were under-expressed in DSS-treated UC. IGF2BP2 enhanced the stability of GPX4 mRNA modified by m6A. IGF2BP2 overexpression repressed the ROS, MDA, and iron levels but enhanced the GSH and GPX4 levels in DSS-triggered NCM460 cells, which were partially reversed by GPX4 silencing. In UC mice, IGF2BP2 high-expression ameliorated symptoms, Disease Activity Index score, pathological changes, inflammatory reaction, and ferroptosis, which were also partly neutralized by GPX4 inhibition. Conclusions: IGF2BP2 augmented the GPX4 expression by the m6A modification to weaken UC progression via suppressing ferroptosis.

Automated summary

IGF2BP2 enhances the expression of GPX4 through m6A modification, thereby suppressing ferroptosis and attenuating inflammation and pathological changes in ulcerative colitis.