In this study, we examined the role of Nrf2 and AKR1C1 in the process of progestin resistance with the following approaches: 1) to test the level of Nrf2 and AKR1C1 protein expression in progestin treated endometrial cancer samples; 2) to examine the progestin resistance through up- or down-regulation of Nrf2 and AKR1C1 expression in 2 endometrial cancer cell lines; and 3) to test if the progestin resistance could be reversed by addition of metformin and brusatol, and the effects of these agents on Nrf2 and AKR1C1 expression. The gene discussed is AKR1C1; the disease is endometrial cancer.