Nrf2 (NF-E2-related factor 2) and INrf2 (Keap1) are cellular sensors of oxidative and electrophilic stress. Nrf2 is a nuclear transcription factor that controls the expression of a battery of defensive genes encoding detoxifying enzymes and antioxidant proteins, which is crucial for cellular protection and survival. Nrf2 is retained in the cytoplasm by INrf2, which functions as an adapter for the Cul3/Rbx1-mediated degradation of Nrf2. In response to oxidative/electrophilic stress, Nrf2 is activated and then deactivated through distinct early and delayed mechanisms. Oxidative/electrophilic modification of INrf2's cysteine 151 and/or PKC phosphorylation of Nrf2's serine 40 result in the release of Nrf2 from INrf2. Nrf2 is stabilized, translocates to the nucleus, forms heterodimers with unknown proteins, and binds to the antioxidant response element (ARE) to activate gene expression. This process occurs within 15 minutes of exposure to oxidative/electrophilic stress. The delayed mechanism involves GSK3β phosphorylating Fyn at an unknown threonine residue, leading to Fyn's phosphorylation of Nrf2's tyrosine 568, resulting in Nrf2's nuclear export, binding with INrf2, and degradation. The activation and deactivation of Nrf2 protect cells against free radical damage, prevent apoptosis, and promote cell survival.Nrf2 (NF-E2-related factor 2) and INrf2 (Keap1) are cellular sensors of oxidative and electrophilic stress. Nrf2 is a nuclear transcription factor that controls the expression of a battery of defensive genes encoding detoxifying enzymes and antioxidant proteins, which is crucial for cellular protection and survival. Nrf2 is retained in the cytoplasm by INrf2, which functions as an adapter for the Cul3/Rbx1-mediated degradation of Nrf2. In response to oxidative/electrophilic stress, Nrf2 is activated and then deactivated through distinct early and delayed mechanisms. Oxidative/electrophilic modification of INrf2's cysteine 151 and/or PKC phosphorylation of Nrf2's serine 40 result in the release of Nrf2 from INrf2. Nrf2 is stabilized, translocates to the nucleus, forms heterodimers with unknown proteins, and binds to the antioxidant response element (ARE) to activate gene expression. This process occurs within 15 minutes of exposure to oxidative/electrophilic stress. The delayed mechanism involves GSK3β phosphorylating Fyn at an unknown threonine residue, leading to Fyn's phosphorylation of Nrf2's tyrosine 568, resulting in Nrf2's nuclear export, binding with INrf2, and degradation. The activation and deactivation of Nrf2 protect cells against free radical damage, prevent apoptosis, and promote cell survival.