Nrf2

Nrf2, short for nuclear factor erythroid 2–related factor 2, is a transcription factor encoded by the human NFE2L2 gene. It belongs to the CNC-bZIP family and acts as a master regulator of the cellular antioxidant response. Through binding to antioxidant response elements (ARE) in the promoters of target genes, Nrf2 coordinates the induction of antioxidant, detoxification, and cytoprotective genes in response to oxidative and electrophilic stress.

Under basal conditions, Nrf2 is kept at low levels in the cytoplasm by KEAP1, which targets it for ubiquitin-dependent degradation via the CUL3-Rbx1 E3 ligase complex. Oxidative or electrophilic modification of KEAP1 cysteine residues disrupts this interaction, allowing Nrf2 to accumulate, translocate to the nucleus, dimerize with small Maf proteins, and bind ARE to activate genes such as NQO1, HO-1, GCLC, and GCLM, as well as various glutathione and drug-metabolizing enzymes. Additional regulation involves the p62 pathway and a KEAP1-independent GSK-3β/beta-TrCP axis that can promote Nrf2 degradation.

Nrf2 activity supports redox balance, mitochondrial function, and metabolic adaptation, and modulates inflammation. In animal and human studies, proper Nrf2 function is associated with protection against neurodegenerative disease, cardiovascular injury, and liver damage. Dysregulation can contribute to pathology; insufficient Nrf2 increases susceptibility to oxidative stress, whereas constitutive activation of Nrf2 has been implicated in cancer cell survival and chemoresistance.

Therapeutic interest centers on Nrf2 activators that enhance cytoprotective gene expression, including natural compounds such as sulforaphane and synthetic agents like bardoxolone methyl. While NRF2 activation holds potential for preventing or treating chronic diseases, it must be approached with care given potential pro-tumor effects and variable responses across tissues and conditions.