Ythdf1 deficiency exacerbates colitis but prevents colitis-associated cancer in mice

Aims: Recurrent and uncontrolled inflammation of the colon may cause inflammatory bowel diseases (IBD), which are strongly associated with the onset of colitis-associated cancer (CAC). However, the molecular mechanisms linking inflammation, dysregulated growth, and tumorigenesis remain unclear. This study aims to determine the role of the N6-methyladenosine (m6A) reader YTH m6A RNA binding protein 1 (Ythdf1) in regulating colitis severity and CAC development. Methods: Ythdf1-deficient and wild-type mice were subjected to dextran sodium sulfate (DSS)-induced colitis to evaluate disease severity, epithelial survival, goblet cell and mucus preservation, and inflammatory signaling. m6A-dependent regulation of Jak1 mRNA and the Il6-Jak1-Stat3 pathway activation was assessed through molecular analyses. Additionally, an azoxymethane (AOM)/DSS model was used to determine the impact of Ythdf1 loss on CAC development. Results: Ythdf1 deficiency significantly worsened DSS-induced colitis, with increased epithelial damage, loss of goblet cells and mucus, impaired epithelial survival, and reduced Stat3 activation. Mechanistically, Ythdf1 recognized m6A-modified Jak1 mRNA and enhanced Jak1 protein expression, thereby maintaining the Il6-Jak1-Stat3 signaling during inflammatory stress. Despite aggravating colitis, Ythdf1 loss markedly suppressed CAC progression and reduced tumor burden. Conclusion: Ythdf1 is a key regulator of intestinal homeostasis, maintaining the Il6-Jak1-Stat3 signaling to protect against colitis while paradoxically promoting CAC progression. These findings identify Ythdf1 as a context-dependent modulator of intestinal inflammation and tumorigenesis, highlighting its therapeutic potential in IBD and CAC.