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The charged nature of GSH (negative at physiological pH) suggests that GSH cannot passively diffuse into the mitochondria, because the mitochondrial matrix has a negative potential relative to the cytoplasm

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Conversely, KEAP1 downregulation (Supplementary Figure S6E) sensitised EGFRm/T790M PC9ER cells to erlotinib (Figure 3g), accompanied by the increased GSH levels (Figure 3h) and increased transcription of GSH-synthesising enzymes GCLC, GSR and GSS (Supplementary Figure S6F)

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Here, we addressed our mechanistic models experimentally using ScGrx7 as a reference enzyme 11,12,18