Fisetin mitigates radiation-induced intestinal injury by inhibiting apoptosis and reconstructing the gut microbiota

Fisetin, a natural flavonoid compound widely present in fruits and vegetables, such as strawberries and onions, is renowned for its antioxidant and anti-inflammatory properties. Radiation-induced intestinal injury (RIII) presents a significant challenge in radiotherapy, especially for patients undergoing treatment in pelvic, abdominal, and colorectal regions. Effective clinical strategies for managing RIII are limited. Our study aimed to investigate the protective potential of fisetin against RIII and elucidate its underlying mechanisms. In this study, we found that fisetin significantly mitigates ionizing radiation-induced apoptosis in IEC6 cells and reduces intestinal organoid damage in vitro. Furthermore, fisetin significantly improved the survival rates of irradiated mice by alleviating pathological structural damage in the intestinal villous-crypt, enhancing crypt cell proliferation and differentiation, and inhibiting apoptosis in vivo. Mechanistically, fisetin mitigates radiation-induced intestinal injury by activating the NRF2 antioxidant pathway, thereby reducing oxidative stress in small intestinal crypt cells. This reduction in oxidative stress subsequently inhibits DNA damage, prevents excessive activation of P53, and diminishes intestinal apoptosis, ultimately contributing to the therapy of RIII. Additionally, fisetin facilitates recovery by modulating and reconstructing the gut microbiota. Our findings suggest that fisetin holds potential as a candidate for managing radiotherapy and mitigating side effects in cases of accidental radiation exposure.