Nrf2 is a key transcription factor that regulates the expression of genes involved in detoxification and antioxidant defense, protecting cells from oxidative and electrophilic stress. Nrf2 is normally retained in the cytoplasm by its inhibitor, INrf2 (Keap1), which acts as an adapter for the Cul3/Rbx1 E3 ubiquitin ligase complex. Under oxidative/electrophilic stress, Nrf2 is released from INrf2, stabilizes, and translocates to the nucleus, where it binds to the antioxidant response element (ARE) to activate gene expression. This process is followed by a delayed mechanism involving GSK3β and Fyn, which leads to the nuclear export and degradation of Nrf2, thereby switching off its activity. Nrf2 plays a critical role in cellular protection against oxidative stress, preventing apoptosis, and promoting cell survival. The Nrf2 pathway is essential for the body's defense against a wide range of stressors, including xenobiotics, heavy metals, and ionizing radiation. Nrf2 is involved in the regulation of various genes, including those encoding detoxifying enzymes and antioxidant proteins, and its dysfunction can lead to increased susceptibility to diseases such as cancer. The Nrf2 pathway is also implicated in drug resistance, with Nrf2 activation contributing to the detoxification of chemotherapeutic agents. Understanding the regulation of Nrf2 is crucial for developing new chemopreventive compounds and therapeutic strategies.Nrf2 is a key transcription factor that regulates the expression of genes involved in detoxification and antioxidant defense, protecting cells from oxidative and electrophilic stress. Nrf2 is normally retained in the cytoplasm by its inhibitor, INrf2 (Keap1), which acts as an adapter for the Cul3/Rbx1 E3 ubiquitin ligase complex. Under oxidative/electrophilic stress, Nrf2 is released from INrf2, stabilizes, and translocates to the nucleus, where it binds to the antioxidant response element (ARE) to activate gene expression. This process is followed by a delayed mechanism involving GSK3β and Fyn, which leads to the nuclear export and degradation of Nrf2, thereby switching off its activity. Nrf2 plays a critical role in cellular protection against oxidative stress, preventing apoptosis, and promoting cell survival. The Nrf2 pathway is essential for the body's defense against a wide range of stressors, including xenobiotics, heavy metals, and ionizing radiation. Nrf2 is involved in the regulation of various genes, including those encoding detoxifying enzymes and antioxidant proteins, and its dysfunction can lead to increased susceptibility to diseases such as cancer. The Nrf2 pathway is also implicated in drug resistance, with Nrf2 activation contributing to the detoxification of chemotherapeutic agents. Understanding the regulation of Nrf2 is crucial for developing new chemopreventive compounds and therapeutic strategies.