In the current study, we explored the effect of LDR on theactivation of Nrfs transcription factor involved in cellular redoxevents. Experiments were carried out utilizing 0.05 and 0.5 GyX-ray irradiated normal human skin fibroblast HS27 cells. Theresults showed LDR induced Nrf1 and Nrf2 activation andexpression of antioxidant genes HO-1, Mn-SOD, and NQO1.In particular, 0.05 Gy-irradiation increased only Nrf1 activation,but 0.5 Gy induced both Nrf1 and Nrf2 activation.LDR-mediated Nrf1/2 activation was accompanied by reactivespecies (RS) generation and Ca2+ flux. This effect was abolishedin the presence of N-acetyl-cysteine and BAPTA- AM.Furthermore, Nrf1/2 activation by LDR was suppressed byPD98059, an inhibitor of ERK1/2. In conclusion, LDR inducesNrf1 and Nrf2 activation and expression of Nrf-regulatedantioxidant defense genes through RS and Ca2+/ERK1/2pathways, suggesting new insights into the molecularmechanism underlying the beneficial role of LDR in HS27cells. [BMB Reports 2013; 46(5): 258-263]