YTHDF1 activates FBW7 transcription by regulating m6A-dependent FOXO1 to facilitate inflammatory response in ulcerative colitis-like model.

The prevalence of inflammatory bowel disease (IBD) has increased recently and lacks curative treatments. The involvement of the N6-methyladenosine (m6A) reader YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) in ulcerative colitis (UC)-like model was studied in this study. DSS was employed to induce the UC-like condition both in vitro and in vivo. TNF-α, IL-1β, IL-6, and IL-8 secretion levels were analyzed by ELISA assay. Cell vitality was determined by CCK8 assay. FOXO1 mRNA m6A level was examined using methylated RNA binding protein immunoprecipitation (Me-RIP) assay. The interactions between YTHDF1 and FOXO1 were analyzed by RIP assay. ChIP and dual luciferase reporter assays were used to explore the relationship between FOXO1 and FBW7. YTHDF1, FOXO1, and FBW7 were overexpressed in DSS-induced colon epithelial cells. YTHDF1 downregulation alleviated DSS-induced inflammation and NF-κB signal activation in colon epithelial cells. Mechanically, YTHDF1 increased FOXO1 mRNA stability in an m6A manner. YTHDF1 overexpression prevented the inhibition of FOXO1 knockdown on DSS-induced inflammation in colon epithelial cells. In addition, FOXO1 transcriptionally activated FBW7. Moreover, FOXO1 upregulation abolished the inhibitory effect of FBW7 knockdown on DSS-induced inflammation in colon epithelial cells. Animal experiments also showed that YTHDF1 deletion alleviated inflammatory response in UC-like mice. YTHDF1 promoted inflammatory response in the UC-like model by transcriptionally activating FBW7 through regulating m6A-dependent FOXO1.