OGT Orchestrates Intestinal Epithelial Homeostasis and Repair through Coordinated mTORC1 Activity

Conversely, low‑dose rapamycin treatment in OGT‑deficient mice markedly attenuated mTORC1 hyperactivation and substantially improved epithelial regeneration after irradiation. Consistently, OGT‑deficient organoids exhibited heightened sensitivity to irradiation, which was alleviated by rapamycin. Furthermore, pharmacological elevation of O‑GlcNAcylation using the OGA inhibitor Thiamet‑G protected high‑fat diet‑fed mice from irradiation‑induced intestinal damage and promoted epithelial repair.

Collectively, our findings establish OGT‑mediated O‑GlcNAcylation as a critical regulator of ISC function and mucosal repair through metabolic control of mTORC1 activity, and suggest that enhancing O‑GlcNAc signaling may represent a therapeutic strategy for radiation‑induced intestinal injury.