Increased antioxidative defense and reduced advanced glycation end-product formation by metabolic adaptation in non-small-cell-lung-cancer patients

Tamara Tomin, Sophie Elisabeth Honeder, Laura Liesinger, Daniela Gremel, Bernhard Retzl, Joerg Lindenmann, Luka Brcic, Matthias Schittmayer () and Ruth Birner-Gruenberger ()
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Tamara Tomin: TU Wien
Sophie Elisabeth Honeder: TU Wien
Laura Liesinger: TU Wien
Daniela Gremel: TU Wien
Bernhard Retzl: TU Wien
Joerg Lindenmann: Medical University of Graz
Luka Brcic: Medical University of Vienna
Matthias Schittmayer: TU Wien
Ruth Birner-Gruenberger: TU Wien

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Reactive oxygen species can oxidatively modify enzymes to reroute metabolism according to tumor needs, rendering identification of oxidized proteins important for understanding neoplastic survival mechanisms. Thiol groups are most susceptible to oxidative modifications but challenging to analyze in clinical settings. We here describe the protein and small-molecular thiol oxidation landscape of 70 human lung tumors (and their paired healthy counter parts) and demonstrate that cancer adapts metabolism to increase glutathione synthesis to counteract oxidative stress. Glyoxalases, the key enzymes in the detoxification of methylglyoxal, a byproduct of glycolysis and precursor of advanced glycation end-products, are compromised by oxidation and downregulation. Despite decreased methylglyoxal detoxification capacity, cancers do not accumulate advanced glycation end-products. Since in vitro downregulation or inhibition of GAPDH upregulates glyoxalases, we propose that tumors reduce methylglyoxal by activating GAPDH.

Date: 2025
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DOI: 10.1038/s41467-025-60326-y

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