The Keap1/Nrf2 pathway and its epigenetic modification by SFN. Under basal conditions, Keap1 binds to Nrf2 in the cytoplasm, which promotes its proteasomal degradation via ubiquitination. Under oxidative stress, Nrf2 dissociates from Keap1 and then translocates into the nucleus and binds with the small protein Maf at ARE sequences in the promoter regions of target genes. This drives the expression of several cytoprotective genes, such as HO-1, NQO1, and SOD. In TRAMP C1 prostate cancer cells, SFN can inhibit the expression and activity of enzymes involved in epigenetic regulation, including DNMT1 and 3a, as well as HDAC1, 4, 5, and 7. Significant inhibition of DNMT1, DNMT3a/b, and HDAC1, 2, 3, and 4 has also been observed in TPA-induced mouse skin JB6 P+ cells treated by SFN, which reduces the CpG methylation and elevates histone acetylation of the Nrf2 promoter. Ultimately, epigenetic regulation by SFN promotes the transcription of Nrf2 and its subsequent nuclear translocation and activation.