Crosstalk Between Nrf2 and Metabolic Pathways: Redox Regulation, Glutaminolysis, and Cellular Proliferation

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) was first described as a cytoprotective regulator that switches on antioxidant and detoxification genes through the antioxidant response element (ARE). That view is accurate but incomplete. Nrf2 also controls metabolic genes governing the pentose phosphate pathway, glutamine catabolism, regeneration of reduced nicotinamide adenine dinucleotide phosphate (NADPH), fatty acid handling, purine synthesis and iron storage, placing it where antioxidant defence and biosynthesis draw on shared pools of carbon, nitrogen and reducing equivalents. This critical narrative review, assembled purposively from PubMed, MEDLINE and Google Scholar rather than systematically, examines the Nrf2/Keap1 axis and then the point where Nrf2 partitions glutamate between anaplerotic entry into the tricarboxylic acid cycle and glutathione synthesis. Stable-isotope tracing shows this partitioning to be measurable as flux: Nrf2 activation raises both glutamate consumption for glutathione and glutamate export through system xc⁻, limiting the carbon available to central metabolism and creating dependency on exogenous glutamine. The same arithmetic accounts for tanshinone IIA starving proliferating myofibroblasts in pulmonary fibrosis and, in the diabetic heart, for Nrf2 repressing thioredoxin-interacting protein at an ARE to protect cardiomyocytes. We argue that the contested dual role of Nrf2 in tumour progression follows from this logic: Nrf2 supplies substrate rather than a proliferative instruction, so the direction of its effect is set by whether the cell carries demand able to consume that substrate and a checkpoint able to restrain its use. We close on tissue context and on matching Nrf2-directed compounds to tissue metabolic state.