Sitagliptin Alleviates Radiation‐Induced Intestinal Injury by Activating NRF2‐Antioxidant Axis, Mitigating NLRP3 Inf‐‐lammasome Activation, and Reversing Gut Microbiota Disorder

Radiation‐induced intestinal injury is a common and critical complication of radiotherapy for pelvic or abdominal tumors, with limited therapeutic strategies and effectiveness. Sitagliptin, a dipeptidyl peptidase IV (DPP4) inhibitor, has previously been reported to alleviate total body irradiation‐ (TBI‐) induced damage of hematopoietic system in mice, but its effect on radiation‐induced intestinal injury remains unclear. In this study, we confirmed that Sitagliptin could not only protect mice from death and weight loss caused by whole abdominal irradiation (WAI) but also improve the morphological structure of intestine and the regeneration ability of enterocytes. In addition, Sitagliptin significantly inhibited the production of radiation‐induced proinflammatory cytokines and reduced the number of apoptotic intestinal epithelial cells and γ‐H2AX expression. In vitro, we demonstrated that Sitagliptin protected HIEC‐6 cells from ionizing radiation, resulting in increased cell viability and reduced DNA damage. Mechanistically, the radiation protection of Sitagliptin might be related to the upregulation of NRF2 level and the decrease of NLRP3 inflammasome activity. Importantly, Sitagliptin significantly restored radiation‐induced changes in bacterial composition. In conclusion, our results suggested that Sitagliptin could reduce WAI‐induced intestinal injury in mice, which may provide novel therapeutic strategy for radiation‐induced intestinal injury.