Fig. 1.

Glutaminolysis promotes ROS detoxification and redox homeostasis in cancer through TCA cycle intermediates. Upregulated GDH1 and other enzymes involved in glutaminolysis maintain increased levels of ⍺-KG and downstream TCA metabolites such as fumarate and malate. Fumarate modulates cysteine residues on Keap-1 to promote antioxidant gene expression through the Nrf-2 transcription factor, and also enhances the antioxidant activity of GPx1. Conversion of malate to oxaloacetate via malate dehydrogenase regenerates NADP + to NADPH, which can directly detoxify mitochondrial ROS or maintain intracellular pools of reduced glutathione.