ABSTRACT Tumor cells acquire the ability to reprogram their energy metabolism in response to environmental stresses such as hypoxia, oxidative stress, and therapeutic effects. Key factors driving this adaptive shift include Nrf2, a master transcriptional regulator of redox homeostasis and intermediary metabolism, and activation of associated signaling pathways. Nrf2 is known to play a role in regulating glycolysis, lipid metabolism, and amino acid turnover, each of which contributes to the emergence and maintenance of drug resistance. Activated Nrf2 can bind to AREs in the promoters of cytoprotective genes involved in glutathione biosynthesis, NADPH regeneration, and xenobiotic metabolism, thereby promoting both tumor progression and cell death by promoting p53 accumulation. Through transcriptional activation of genes involved in antioxidant defense and detoxification, Nrf2 protects cancer cells from oxidative damage and chemotherapeutic effects. Targeting Nrf2 glycation pathways is important as a strategy to enhance the efficacy of pro-oxidant therapies and weaken tumor antioxidant defenses. All of these transcriptional reprogrammings promote cellular survival by facilitating the detoxification of ROS, restoration of redox homeostasis, and repair of oxidative lesions. Under basal conditions, Nrf2 is ubiquitinated and degraded in the cytoplasm by Keap1. Increased ROS levels resulting from oncometabolite accumulation in tumorigenesis modify cysteine residues on Keap1, weakening its ability to target Nrf2 for degradation. This allows Nrf2 to translocate to the nucleus, where it activates the transcription of ARE-driven genes, enhancing cellular antioxidant capacity and supporting survival under oxidative stress. All of these reprogramming processes mentioned by NRF2 in cancer, particularly glycolysis, glutaminolysis, and redox buffering, are critical for supporting metabolic reprogramming and stress adaptation, including anabolic growth in cancer cells.