Oxidative stress is one of the important factors to induce carcinogenesis, including skin cancers. Many bioactivities of polymethoxyflavones (PMFs), such as tangeretin and nobiletin, in citrus peels have been studied. In this study, the cancer chemopreventive potential potential and mechanism of tangeretin and nobiletin metabolites with low cytotoxicity were investigated. The results showed that PMF‐2, a tangertin derivate, at 50 μM showed the strongest activity to trigger Nrf2 pathway in human hepatoma HepG2‐C8 cells that were stably transfected with Nrf2‐antioxidant response element (ARE)‐luciferase plasmids. PMF‐2 also significantly suppressed 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA)‐induced anchorage independent growth of mouse skin JB6 P+ cells. Additionally, PMF‐2 increased mRNA and protein expression of Nrf2 and Nrf2 downstream genes such as heme oxygenase‐1 (HO‐1), NAD(P)H dehydrogenase quinone 1 (NQO1), and UDP glucuronosyltransferase 1A (UGT1A). Furthermore, PMF‐2 might regulate the expression of Nrf2 and Nrf2 downstream genes through regulating DNA methylation and Histone modification, which was elucidated by the determination of DNMTs, HDACs, and KDMs protein expressions, in vitro DNA methylation, methylation‐specific PCR (MSP) of Nrf2 promoter. The relationship between Nrf2 downstream genes and histone H3 acetylation (H3ac) was also analyzed by chromatin immunoprecipitation (ChIP)‐qPCR assay. Therefore, PMF‐2 has skin cancer chemopreventive potential through activating Nrf2‐related pathway that might be regulated by epigenetics modification.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.