Psoralen alleviates radiation-induced bone injury by rescuing skeletal stem cell stemness through AKT-mediated upregulation of GSK-3β and NRF2

Background: Repairing radiation-induced bone injuries remains a significant challenge in the clinic, and few effective medicines are currently available. Psoralen is a principal bioactive component of Cullen corylifolium (L.) Medik and has been reported to have antitumor, anti-inflammatory, and pro-osteogenesis activities. However, less information is available regarding the role of psoralen in the treatment of radiation-induced bone injury. In this study, we explored the modulatory effects of psoralen on skeletal stem cells and their protective effects on radiation-induced bone injuries. Methods: The protective effects of psoralen on radiation-induced osteoporosis and irradiated bone defects were evaluated by microCT and pathological analysis. In addition, the cell proliferation, osteogenesis, and self-renewal of SSCs were explored. Further, the underlying mechanisms of the protective of psoralen were investigated by using RNA sequencing and functional gain and loss experiments in vitro and in vivo. Statistical significance was analyzed using Student's t test. The one-way ANOVA was used in multiple group data analysis. Results: Here, we demonstrated that psoralen, a natural herbal extract, mitigated radiation-induced bone injury (irradiation-induced osteoporosis and irradiated bone defects) in mice partially by rescuing the stemness of irradiated skeletal stem cells. Mechanistically, psoralen restored the stemness of skeletal stem cells by alleviating the radiation-induced suppression of AKT/GSK-3 beta and elevating NRF2 expression in skeletal stem cells. Furthermore, the expression of KEAP1 in skeletal stem cells did not significantly change in the presence of psoralen. Moreover, blockade of NRF2 in vivo partially abolished the promising effects of psoralen in a murine model of irradiation-induced osteoporosis and irradiated bone regeneration. Conclusions: In summary, our findings identified psoralen as a potential medicine to mitigate bone radiation injury. In addition, skeletal stem cells and AKT-GSK-3 beta and NRF2 may thus represent therapeutic targets for treating radiation-induced bone injury.