FIH‐1 Deletion in Intestinal Epithelial Cells Causes Radioprotection by Activating PI3K‐AKT Pathway

Radiotherapy is used as adjuvant and radical treatment for pelvic and abdominal tumors, while radiation‐induced gastrointestinal syndrome (RIGS) severely affects patients' quality of life and even terminates the treatment process. Inhibiting asparagine hydroxylase (FIH‐1) has been demonstrated to be an effective strategy for alleviating the syndrome, suggesting it may serve as a potential therapeutic target for the treatment of RIGS. Therefore, we aimed to elucidate the crucial regulatory mechanisms involved in the radioprotection of RIGS after FIH‐1 deletion. We constructed FIH‐1 ‐silenced cells in the human intestinal epithelial cell line (HIEC‐6) and evaluated their radiosensitivity through colony formation assay, cell cycle analysis, and apoptosis assay. RNA‐Seq analysis and western blotting were further utilized to reveal the mechanism of radioresistance in the shFIH‐1 cell line. FIH‐1 deficiency mitigated radiation‐induced cell damage through accelerating proliferation and enhancing cell cycle redistribution in S‐phase. RNA‐Seq analysis and western blotting further presented that PI3K‐AKT and cell cycle signaling pathways were remarkably upregulated in the shFIH‐1 cells. All these results indicated that the activation of the PI3K‐AKT pathway and cell cycle redistribution upon FIH‐1 deficiency is the primary reason for its radioprotection of RIGS.