Fig. 6. Working model depicting how different expression levels of SLC7A11 dictate differential responses to oxidative stress in cancer cells.

a SLC7A11 imports cystine into cells to produce GSH, which can detoxify H₂O₂. However, both the reduction of cystine to cysteine and that of GSSG to GSH consume NADPH. b In cells with moderate expression of SLC7A11, the beneficial effect of GSH to detoxify H₂O₂ appears to be stronger than the NADPH-depleting effect of cystine reduction, resulting in decreased sensitivity to H₂O₂. c In cells with high expression of SLC7A11 and high cystine uptake, H₂O₂ treatment leads to drastic accumulation of intracellular cystine and other disulfide molecules and NADPH depletion, which overrides the beneficial effect of GSH and triggers rapid disulfidptosis. This explains the increased sensitivity to H₂O₂ in SLC7A11-high cells. NADPH nicotinamide adenine dinucleotide phosphate, GSH reduced glutathione, GSSG glutathione disulfide.