This study investigates the dysfunctional interaction between KEAP1 and NRF2 in non-small-cell lung cancer (NSCLC). KEAP1 is a negative regulator of NRF2, which is a redox-sensitive transcription factor that promotes the expression of genes involved in antioxidant defense, xenobiotic detoxification, and drug efflux. Mutations in KEAP1 lead to its inactivation, resulting in constitutive activation of NRF2, which enhances the expression of genes that confer resistance to chemotherapy. The study found that biallelic inactivation of KEAP1 is a common event in NSCLC, with mutations in KEAP1 detected in 50% of cell lines and 19% of tumors. These mutations are located in highly conserved regions of KEAP1, suggesting they may impair its repressor activity. Loss of heterozygosity at 19p13.2, where KEAP1 is located, was observed in a significant proportion of NSCLC samples. The loss of KEAP1 function leads to increased nuclear accumulation of NRF2, which in turn enhances the expression of antioxidant and detoxification genes, contributing to chemoresistance. The study also shows that NRF2 activation is associated with increased expression of drug efflux pumps and detoxification enzymes, which may help cancer cells survive chemotherapy. These findings suggest that the KEAP1-NRF2 pathway plays a critical role in the survival and chemoresistance of NSCLC cells. The study highlights the importance of KEAP1 in maintaining normal NRF2 activity and suggests that mutations in KEAP1 may contribute to the development of NSCLC. The results provide new insights into the molecular mechanisms underlying chemoresistance in NSCLC and may have implications for the development of new therapeutic strategies targeting the NRF2 pathway.This study investigates the dysfunctional interaction between KEAP1 and NRF2 in non-small-cell lung cancer (NSCLC). KEAP1 is a negative regulator of NRF2, which is a redox-sensitive transcription factor that promotes the expression of genes involved in antioxidant defense, xenobiotic detoxification, and drug efflux. Mutations in KEAP1 lead to its inactivation, resulting in constitutive activation of NRF2, which enhances the expression of genes that confer resistance to chemotherapy. The study found that biallelic inactivation of KEAP1 is a common event in NSCLC, with mutations in KEAP1 detected in 50% of cell lines and 19% of tumors. These mutations are located in highly conserved regions of KEAP1, suggesting they may impair its repressor activity. Loss of heterozygosity at 19p13.2, where KEAP1 is located, was observed in a significant proportion of NSCLC samples. The loss of KEAP1 function leads to increased nuclear accumulation of NRF2, which in turn enhances the expression of antioxidant and detoxification genes, contributing to chemoresistance. The study also shows that NRF2 activation is associated with increased expression of drug efflux pumps and detoxification enzymes, which may help cancer cells survive chemotherapy. These findings suggest that the KEAP1-NRF2 pathway plays a critical role in the survival and chemoresistance of NSCLC cells. The study highlights the importance of KEAP1 in maintaining normal NRF2 activity and suggests that mutations in KEAP1 may contribute to the development of NSCLC. The results provide new insights into the molecular mechanisms underlying chemoresistance in NSCLC and may have implications for the development of new therapeutic strategies targeting the NRF2 pathway.