Impaired colonic mucosal repair is a critical issue in inflammatory bowel diseases (IBD). SATB2 is essential for maintaining colonic epithelial homeostasis, but its role in mucosal repair is unclear. In this study, flow cytometry was used to assess SATB2's role in colonic epithelial repair in a radiation injury model. SATB2 knockout mice exhibited defective epithelial repair, with a marked reduction in goblet and enteroendocrine cells. Mechanistically, SATB2 directly regulated PPAR-gamma transcription, and PYY was observed to translocate into the nucleus and promote the transcription of PPAR-gamma target genes. In organoids derived from patients with Crohn's disease, PYY supplementation significantly improved epithelial regeneration, outperforming the PPAR-gamma agonist rosiglitazone. In conclusion, SATB2 deficiency impairs colonic epithelial repair, which can be rescued by PYY through activation of PPAR-gamma-dependent transcription. These findings suggest that PYY may serve as a promising therapeutic molecule to promote epithelial repair in IBD.