Study identifies backup pathway that lets cells make cysteine without major disulfide reductases

Researchers have identified a previously unrecognized backup pathway that allows mammalian cells to keep making cysteine even when the two major cellular systems long thought necessary for that job are shut down, according to a peer-reviewed study published May 21, 2026, in Nature Chemical Biology. The finding matters not just because it revises a basic assumption in cell biology, but also because it could help explain how some cancer cells survive efforts to cut off cysteine supplies and weaken antioxidant defenses.

Cysteine is a sulfur-containing amino acid that cells need to build proteins, manage sulfur chemistry and, crucially, make glutathione, a major antioxidant. Many tumors are known to depend heavily on cystine import and glutathione metabolism, making those pathways a target for strategies tied to oxidative stress and ferroptosis, a form of cell death driven by lipid damage. The new work suggests cells may have a metabolic bypass when standard cystine-reduction machinery is unavailable.

The study, titled “Cystine C–S bond cleavage fuels cysteine production under disulfide reductase deficiency,” was led by Edward E. Schmidt of Montana State University, with collaborators at the Hungarian National Institute of Oncology, the University of Veterinary Medicine Budapest and H. Lee Moffitt Cancer Center. In core experiments, the researchers used genetically engineered mouse livers and liver cells lacking thioredoxin reductase 1 and glutathione reductase, the two main cytosolic disulfide reductases. These “TR/GR-null” cells were expected to struggle to turn imported cystine into usable cysteine.

Instead, the cells kept making cysteine. “This was supposed to be impossible,” Schmidt said, as quoted by ScienceDaily in a summary of Montana State University materials posted Sept. 24.

The paper’s central finding is that, in the absence of the canonical reductase systems, cells can draw cysteine from an alternative route: a pyridoxal-phosphate, or PLP, dependent cleavage of a carbon-sulfur bond in cystine. That reaction produces cysteine persulfide, which then breaks down nonenzymatically into cysteine. The authors reported that most cysteine in TR/GR-null livers came from this pathway, which they described as a previously unrecognized cytoprotective response. They also suggested it may be inducible in many mammalian cells when cytosolic cystine stays chronically elevated.

The evidence came from several lines of work, including steady-state metabolomics, in vivo isotope tracing in mice, liquid chromatography-mass spectrometry measurements of sulfur metabolites, experiments in primary hepatocytes and liver lysates, and inhibitor studies used to probe PLP-dependent enzymes. Together, those approaches pointed to cystine bond cleavage, rather than classical disulfide reduction, as the dominant source of cysteine in the altered mouse liver system.

That result reshapes a long-standing picture of how mammalian cells obtain this amino acid. Before this study, the recognized options were importing cystine and reducing it to cysteine through cellular reductase systems, making cysteine through the transsulfuration pathway from methionine, or, in some settings, drawing on extracellular sulfur sources such as glutathione or proteins. Schmidt said, again as quoted by ScienceDaily, “All cells need a constant supply of an amino acid called cysteine in order to stay alive.”

The cancer implications are suggestive, but still preliminary. Because cysteine is required for glutathione production, any backup route that preserves cysteine could help cells withstand oxidative stress. That makes the newly described pathway a plausible explanation for why some tumors might evade treatments designed to exploit dependence on cystine or antioxidant metabolism.

But the study did not establish that this mechanism broadly operates in human tumors in patients. It demonstrated the pathway in mouse liver and related experimental systems. Any attempt to target it therapeutically would also have to contend with toxicity and specificity, since PLP-dependent sulfur metabolism is part of normal cell function. The authors declared no competing interests.