Loss of Nrf2 accelerates ionizing radiation-induced bone loss by upregulating RANKL

► Accelerated bone loss was noted in mice lacking Nrf2 after radiation. ► Osteoblast mineralization was decreased in Nrf2−/− osteoblasts compared to Nrf2+/+. ► Treatment with N-acetylcysteine (NAC) was able to rescue osteoblast mineralization. ► In mice lacking Nrf2, the expression of RANKL was increased after radiation. ► Prior NAC treatment suppressed RANKL induction in Nrf2−/− osteoblasts.