Nonetheless, the fact that cancer cells can activate NRF2 through several mechanisms, including somatic mutations in Keap1 or NRF2 gene loci, hypermethylation at the promoter region of Keap1, transcriptional upregulation of the NRF2 gene through oncogene-dependent signaling, interruption of Keap1-NRF2 interaction, and the modification of Keap1 protein by electrophilic oncometabolites, may provide possible resolution of this contradiction, in which cancer cells could lose their sensitivity to NRF2 activators [222,223]. Here, NFE2L2 is linked to cancer.