NRF2mediated

NRF2-mediated refers to cellular processes governed by the transcription factor NRF2, which orchestrates protective responses to oxidative and electrophilic stress. NRF2 is a basic leucine zipper transcription factor that regulates the expression of antioxidant, detoxification, and cytoprotective genes by binding to antioxidant response elements (ARE) in gene promoters.

Under basal conditions, NRF2 is kept in the cytoplasm by its inhibitor KEAP1 and targeted for ubiquitin-based degradation. Upon oxidative or electrophilic stress, KEAP1 cysteine residues are modified, releasing NRF2. Freed NRF2 stabilizes and translocates to the nucleus, where it dimerizes with small Maf proteins and binds AREs to activate transcription of target genes involved in glutathione synthesis, NADPH generation, drug metabolism, and redox balance.

Canonical NRF2 targets include NQO1, HMOX1, GCLC, GCLM, GSTs, GPX2, and various phase II detoxification enzymes and transporters. Activation expands the cellular antioxidant capacity and helps neutralize reactive species.

NRF2 activity is modulated by diverse signals, including natural compounds (for example, sulforaphane), drugs (for instance, dimethyl fumarate), and metabolic stress. Negative feedback exists via selective degradation, and cross-talk with other pathways such as NF-κB shapes the outcome of NRF2 signaling.

NRF2-mediated responses contribute to cellular homeostasis in normal tissues and can be protective in liver, lung, and brain. However, persistent NRF2 activation can occur in cancer via KEAP1 or NFE2L2 mutations, promoting chemoresistance and tumor survival. Pharmacologic activation of NRF2 is explored for neurodegenerative and metabolic diseases, though therapeutic use requires careful risk assessment.

Due to context-dependent effects and tissue specificity, the NRF2-mediated pathway remains an active area of research, with ongoing studies to identify selective activators and understand long-term consequences.