The study investigates the role of Nrf2 in ROS (reactive oxygen species) detoxification and tumorigenesis. It finds that oncogenic alleles of K-Ras, B-Raf, and Myc reduce intracellular ROS levels by increasing Nrf2 transcription, which stabilizes Nrf2 and enhances its antioxidant activity. This mechanism is observed in primary murine cells and tissues, as well as in human pancreatic cancer. Genetic targeting of the Nrf2 pathway impairs K-Ras-induced proliferation and tumorigenesis in vivo. The study also reveals that K-RasG12D and B-RafV619E activate Nrf2 through the Raf-MEK-ERK-Jun pathway, and that Nrf2 deficiency reduces proliferation and increases senescence in pancreatic and lung tumors. These findings suggest that constitutively elevated Nrf2 activity in cancer cells can promote tumorigenesis through two mechanisms: diminished Nrf2 turnover and augmented Nrf2 mRNA levels.The study investigates the role of Nrf2 in ROS (reactive oxygen species) detoxification and tumorigenesis. It finds that oncogenic alleles of K-Ras, B-Raf, and Myc reduce intracellular ROS levels by increasing Nrf2 transcription, which stabilizes Nrf2 and enhances its antioxidant activity. This mechanism is observed in primary murine cells and tissues, as well as in human pancreatic cancer. Genetic targeting of the Nrf2 pathway impairs K-Ras-induced proliferation and tumorigenesis in vivo. The study also reveals that K-RasG12D and B-RafV619E activate Nrf2 through the Raf-MEK-ERK-Jun pathway, and that Nrf2 deficiency reduces proliferation and increases senescence in pancreatic and lung tumors. These findings suggest that constitutively elevated Nrf2 activity in cancer cells can promote tumorigenesis through two mechanisms: diminished Nrf2 turnover and augmented Nrf2 mRNA levels.