<p>Radiotherapy is constricted by collateral normal tissue injury during treatment, particularly the gastrointestinal tracts, which is usually referred as radiation-induced gastrointestinal syndrome (RIGS). Currently, there is no FDA-approved agent for the prevention or treatment of RIGS. By using a mice model of RIGS, we demonstrated that 1,2-propanediol (1,2-PD) prevents radiation-induced fatal intestinal injury and significantly increases mice survival following lethal doses of radiation. 1,2-PD pretreatment also enhanced the survival of Lgr5⁺ISCs and improved crypts regeneration after radiation. Moreover, we confirmed 1,2-PD induces dormant cell cycle arrest in enterocytes and ameliorates DNA damage both in vitro and in vivo. Although we did have observed 1,2-PD pretreatment inhibiting P53-PUMA signal pathway, but fail to prove its relation with radiation resistance. In RNA sequencing, we have observed 1,2-PD pretreatment significantly upregulates the Hif-2α, Hif-3α and PPARα target gene ACOX2, whilst downregulating the cell cycle drivers E2f3 and Cyclin D2. These results demonstrate that ISCs play a key role in radiation-induced intestinal regeneration and that 1,2-PD acts as a potent intestinal radioprotector</p>