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Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. The cystine/glutamate antiporter, system x c−, is one of the> 200 cytoprotective proteins controlled by NRF2, which can be non-invasively imaged by (S)-4-(3-18 F-fluoropropyl)-l-glutamate ([18 F] FSPG) positron emission tomography (PET). Through genetic and pharmacologic manipulation, we show that [18 F] FSPG provides a sensitive and specific marker of NRF2 activation in advanced preclinical models of NSCLC. We validate imaging readouts with metabolomic measurements of system x c− activity and their coupling to intracellular glutathione concentration. A redox gene signature was measured in patients from the TRACERx 421 cohort, suggesting an opportunity for patient stratification prior to imaging. Furthermore, we reveal that system x …