KEAP1 (Kelch-like ECH-associated protein 1) serves as a key cellular sensor and regulator of oxidative stress responses through its role as a substrate adapter in the BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex 1. Under normal conditions, KEAP1 binds to the transcription factor NRF2 and targets it for proteasomal degradation, maintaining cellular homeostasis 23. Upon oxidative or electrophilic stress, reactive cysteine residues in KEAP1 undergo covalent modifications that disrupt its interaction with NRF2, leading to NRF2 stabilization and nuclear translocation 14. This derepression mechanism allows rapid activation of cytoprotective gene expression, including antioxidant enzymes and detoxification factors 2. KEAP1 also regulates other substrates including PGAM5, with the KEAP1-PGAM5 complex playing roles in mitochondrial apoptosis pathways 5. The KEAP1-NRF2 system is critically involved in aging-related processes and various diseases including cancer, where concurrent mutations in KEAP1 and STK11 promote ferroptosis resistance in lung adenocarcinoma 6. This pathway represents an important therapeutic target for oxidative stress-related disorders and has significant clinical implications for cancer treatment strategies 7.