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.