Tumours can rewire their metabolism due to activation of the transcription factor NRF2. Brain, Vigil et al. explored the metabolic characteristics of cancer cells with a dependency on NRF2. Using the Cancer Dependency Map and metabolic flux studies, they documented increased cystine consumption. They optimized an untargeted isotope-tracing approach to track the fate of cystine and discovered that some of the cystine fates arose independently of expected pathways. The authors identified previously unknown sugar–cysteine metabolites, including products formed by reversible and irreversible reaction of the thiol group with sugars. Sugar–cysteine conjugates were found in other NRF2-driven tumour models, including a type of human lung tumour. Analyses of cells with varying levels of cystine treatment and usage showed that the free cysteine pool, when high, is associated with production of sugar–cysteine conjugates and proliferation defects.

Although the precise functions or effects of sugar–cysteine conjugates are unclear, this study extends our understanding of excess cysteine stress and of the cysteine metabolome.