Category: signaling
Nrf2 (NFE2L2) is the master transcription factor for antioxidant + phase II detoxification genes. Under basal conditions, Keap1 (cytoplasmic) ubiquitinates Nrf2 → proteasomal degradation. Electrophilic / oxidative stress modifies cysteine residues on Keap1 → Nrf2 released → nuclear translocation → ARE (antioxidant response element) binding → induces HO-1, NQO1, glutathione synthesis, GST, UGT1A enzymes. Many polyphenol + flavonoid + isothiocyanate compounds activate this pathway: sulforaphane (broccoli isothiocyanate — most potent Nrf2 inducer in nature), curcumin, resveratrol, EGCG, quercetin, urolithin-A. Polyphenols are not single-target — they hit Nrf2 + sirtuins + AMPK + cyclic-AMP downstream of metabolite-based signaling. Long-term clinical trials are mostly null for hard outcomes despite robust mechanistic signals — the bioavailability + first-pass conjugation gap remains poorly bridged.