NRF2 / KEAP1

NRF2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that orchestrates the cellular antioxidant and cytoprotective response by binding antioxidant response elements (AREs) in the promoters of genes encoding detoxification enzymes, glutathione synthesis components, proteasome subunits, and anti-inflammatory mediators. Under homeostatic conditions, NRF2 is continuously ubiquitinated by KEAP1 (Kelch-like ECH-associated protein 1), an adaptor for CUL3-based E3 ligase, and targeted for proteasomal degradation; oxidative stress or electrophilic compounds modify critical cysteine residues on KEAP1, impairing its ability to present NRF2 for ubiquitination and allowing NRF2 to accumulate and translocate to the nucleus. NRF2 activity declines with age in multiple tissues, contributing to increased oxidative burden and inflammation; natural compounds such as sulforaphane and pharmacological NRF2 activators are studied for their ability to restore cytoprotective capacity, though the distinction between hormetic activation and potentially tumour-promoting chronic activation warrants caution.