Understanding the molecular mechanisms that regulate intestinal epithelial cell (IEC) renewal provides potential targets for inflammatory bowel disease (IBD). Growing evidence has highlighted the importance of epithelial signals in regulating intestinal stem cell (ISC) differentiation. However, it remains unclear which IEC-derived cytokines can precisely regulate ISC commitment toward specific mature cells. Here we systematically analyze all fibroblast growth factors (FGFs) expression and find that colonic FGF1 levels are inversely correlated with the severity of IBD in mouse models and patients. IEC-specific Fgf1 deletion leads to impaired goblet cell differentiation and exacerbated colitis, while pharmacological administration of recombinant FGF1 (rFGF1) alleviates colitis by enhancing goblet cell differentiation and improving colonic epithelial integrity. Mechanistic studies reveal that rFGF1 directs ISC differentiation toward goblet cells via FGFR2-TCF4-ATOH1 signaling axis. In conclusion, our study identifies an epithelial niche-derived FGF1 that regulates ISC commitment toward goblet cells, shedding light on strategies for treating IBD.
© 2025. The Author(s).