The Keap1-Nrf2 system is a major regulatory pathway that responds to oxidative and electrophilic stresses by activating the transcription factor Nrf2, which in turn induces the expression of cytoprotective genes. Under normal conditions, Keap1 represses Nrf2 activity by promoting its rapid turnover through the ubiquitin-proteasome pathway. However, oxidative and electrophilic stresses modify Keap1, impairing its ability to degrade Nrf2. This study reveals that the Keap1 cysteine residues Cys273 and Cys288 are crucial for this degradation process. Treatment with oxidative or electrophilic agents, or mutation of these residues, impairs Nrf2 degradation but does not affect the association between Keap1 and Nrf2. Instead, these treatments stabilize Nrf2, leading to its accumulation in the nucleus. The results suggest that oxidative and electrophilic stresses activate Nrf2 by disrupting the Keap1-mediated degradation machinery, allowing de novo synthesized Nrf2 to bypass Keap1 and accumulate in the nucleus. This mechanism links the sensing of oxidative and electrophilic stresses to the degradation system of Nrf2, providing insights into the activation of the Nrf2-Keap1 pathway.The Keap1-Nrf2 system is a major regulatory pathway that responds to oxidative and electrophilic stresses by activating the transcription factor Nrf2, which in turn induces the expression of cytoprotective genes. Under normal conditions, Keap1 represses Nrf2 activity by promoting its rapid turnover through the ubiquitin-proteasome pathway. However, oxidative and electrophilic stresses modify Keap1, impairing its ability to degrade Nrf2. This study reveals that the Keap1 cysteine residues Cys273 and Cys288 are crucial for this degradation process. Treatment with oxidative or electrophilic agents, or mutation of these residues, impairs Nrf2 degradation but does not affect the association between Keap1 and Nrf2. Instead, these treatments stabilize Nrf2, leading to its accumulation in the nucleus. The results suggest that oxidative and electrophilic stresses activate Nrf2 by disrupting the Keap1-mediated degradation machinery, allowing de novo synthesized Nrf2 to bypass Keap1 and accumulate in the nucleus. This mechanism links the sensing of oxidative and electrophilic stresses to the degradation system of Nrf2, providing insights into the activation of the Nrf2-Keap1 pathway.