Cancer cells are notorious for rewiring their metabolism to support rapid growth, but sometimes those changes come at a cost. In a new study published in Nature Metabolism, researchers in the Sullivan Lab at Fred Hutch investigated a long-standing mystery surrounding cancers driven by the transcription factor NRF2. They discovered that these tumors consume so much of the nutrient cystine—the oxidized disulfide form of the amino acid cysteine—that it begins reacting with other molecules inside the cell. The resulting buildup of previously unknown compounds is associated with a slowing of cell proliferation and creates a state the researchers call "excess cystine stress."
The study, spearheaded by senior author Dr. Lucas Sullivan and co-lead authors Anna Vigil and Jen Brain, not only uncovers a hidden aspect of cancer metabolism but also suggests a new way to think about targeting tumors that rely on NRF2 signaling. "We've known for years that these cancers take up enormous amounts of cystine," shared Sullivan. "What bothered us was that nobody could really explain where it was all going."
NRF2 helps cells respond to stress by activating genes involved in antioxidant defense and metabolism. In many cancers, however, the pathway becomes permanently switched on, helping tumors survive hostile conditions. One consequence of this constitutive activation is increased expression of a transporter called SLC7A11, which imports cystine into the cytosol where it is rapidly reduced to cysteine. Previous studies had shown that NRF2-activated cancers consume unusually high levels of cystine, but the fate of much of that nutrient remained unknown.
Traditional metabolomics approaches offered only limited answers. While researchers can detect thousands of molecular signals in a sample, most remain unidentified. To tackle the problem, the Sullivan Lab developed an approach that combines isotope tracing with untargeted metabolomics. By feeding cells labeled cystine and tracking where those labels appeared, the researchers could systematically identify molecules derived from cystine metabolism.
The effort revealed dozens of cystine-derived compounds, including many that had never been described before. "We thought there were probably unknown metabolic fates of cystine hiding in these datasets," Sullivan said. "The question was how to find them." The newly identified compounds accumulated at particularly high levels in NRF2-driven cancers. As the researchers investigated further, they realized many of these molecules were not produced by conventional metabolic pathways. Instead, they appeared to arise from spontaneous chemical reactions between cysteine—the intracellular form of cystine—and other cellular metabolites. "To our surprise, it looked like one way cells manage excess cysteine is by conjugating it to other metabolites," said Vigil.
The discovery highlights a largely overlooked aspect of cell biology: metabolites are not simply passive participants in carefully organized pathways. They are also chemical reagents capable of reacting with one another in unexpected ways. "There's a lot of chemistry going on inside cells that we probably don't fully appreciate," Sullivan said. "Many small molecules are reactive, and some of the products they form have gone largely unnoticed." Their work suggests that cells contain a much broader chemical landscape than current metabolic maps capture. To confirm the identities of several newly discovered compounds, the researchers combined cysteine with suspected metabolic intermediates and analyzed the resulting products by mass spectrometry. "It was a very exciting moment seeing those peaks," Vigil said. "It meant all of our expectations and hard work deducing these molecules turned out to be true."
As the team explored the biological consequences of these reactions, a surprising pattern emerged. When researchers increased cystine levels, cancer cells accumulated even more cystine-derived conjugates. At the same time, their growth slowed. Blocking cystine uptake reversed the effect, allowing cells to proliferate normally. The findings suggest that NRF2-driven cancers may experience a unique metabolic burden. Because SLC7A11 continuously imports cystine, the cells can accumulate enough cysteine to trigger widespread chemical reactions with other biomolecules, including intermediates from glycolysis.
"These cells accumulate so much cystine that it begins reacting with normal biomolecules," Sullivan said. "That seemed like it might have consequences." To test whether excess cystine itself was responsible, the researchers used compounds that could temporarily lock cysteine into a nonreactive form. Doing so reduced formation of the conjugates and restored cell proliferation, strengthening the case that excess intracellular cysteine was driving the stress response.
Many efforts to target cancer metabolism focus on depriving tumors of nutrients they depend on. The new findings raise a different possibility: rather than blocking cystine uptake, researchers might be able to exploit the harmful consequences of taking up too much. "We often think, 'This cancer takes up a lot of something, so let's stop it from getting that nutrient,'" Sullivan said. "Another possibility is to lean into the vulnerability that comes from that metabolic behavior."
The concept fits into a broader idea that the Sullivan Lab is exploring: that cancer-causing mutations may create distinct metabolic states, or "metabotypes," that cut across traditional disease categories. Identifying those states could reveal weaknesses shared by tumors with similar metabolic wiring. Although more work is needed to understand exactly how excess cystine impairs cell growth, the study demonstrates that cancer's metabolic adaptations can produce unintended side effects.
By uncovering previously invisible chemistry occurring inside tumor cells, the researchers have opened a new avenue for understanding—and potentially exploiting—the metabolic liabilities of NRF2-driven cancers.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Member Dr. Lucas Sullivan contributed to this research.
The spotlighted research was funded by the National Institutes of Health, the National Science Foundation, and the Emerson Collective Cancer Research Fund.
Brain JA, Vigil ABG, Davidsen K, Itokawa A, Jurasin AC, Kerbyson HJ, Kobiesa M, Hart ML, Yoon SJ, Bellotti P, Maianti JP, DeNicola GM, Sullivan LB. 2026. Excess cysteine drives conjugate formation and impairs proliferation of NRF2-activated cancer cells. Nature Metabolism. DOI: 10.1038/s42255-026-01499-8.
Science Spotlight writer Jenny Waters is a postdoctoral research fellow in the Hsieh lab at Fred Hutch. She studies how mRNA translation coordinates bladder cancer transformation and metastasis by post-transcriptionally regulating expression of oncogenic proteins. Outside of the lab, Jenny enjoys spending time with her dogs, convincing her husband to join her on trail runs, and pretending every steep hill is just a "gentle incline."