β-Cryptoxanthin Confers Radioprotection against Intestinal Injury via NRF2-Mediated Antioxidant Response and Gut Microbiota Reprogramming

Radiation-induced intestinal injury, a common complication of abdominal/pelvic radiotherapy for cancer patients and accidental irradiation, presents a major clinical challenge due to the lack of effective treatments. This study investigates the radioprotective potential of β-cryptoxanthin, a provitamin A carotenoid known for its antioxidant properties. <i>In vivo</i>, oral β-cryptoxanthin administration alleviated radiation-induced intestinal injury by enhancing the NRF2-mediated antioxidant response, which was confirmed by its lack of efficacy in <i>Nrf2^-/-</i> mice. Additionally, it restored radiation-impaired microbiota by increasing beneficial bacterial populations and protective metabolites like short-chain fatty acids (SCFAs), thereby re-establishing a radioprotective gut ecosystem. At the cellular level, β-cryptoxanthin pretreatment significantly improved cell viability and proliferation while reducing reactive oxygen species (ROS), apoptosis, and DNA damage in irradiated MODE-K intestinal epithelial cells. Mechanistically, β-cryptoxanthin activated the AMPK-GSK3β signaling axis, which drove NRF2 nuclear translocation and upregulated NRF2-dependent cytoprotective genes. Knockdown of NRF2 or AMPK abolished the radioprotective effects, confirming the involvement of these pathways. Overall, this study demonstrates that β-cryptoxanthin protects against radiation-induced intestinal injury through dual mechanisms: activating the NRF2-mediated antioxidant response and reprogramming the gut microbiota to restore a radioprotective ecosystem. These findings position β-cryptoxanthin as a promising candidate for clinical radioprotection.