Crosstalk between S-nitrosylation and glycation defines a metabolic vulnerability in liver and renal cancers
Year: 2026
Type: article
Abstract: Metabolic reprogramming is a defining feature of cancer; however, how it contributes to therapeutic resistance remains incompletely understood. Here we show that loss of aldo-ketoreductase 1A1 (AKR1A1) in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) disrupts terminal glycolytic flux and lactate production through S-nitrosylation-mediated inhibition of pyruvate kinase, resulting in the accumulation of methylglyoxal (MGO). In multiple AKR1A1-deficient models, but not in those endogenously expressing the C423/424 A mutant of pyruvate kinase M2, elevated MGO triggers autophagic degradation of Kelch-like ECH-associated protein 1, leading to Nuclear factor erythroid 2-Related Factor 2 (NRF2) activation and transcriptional reprogramming. This NRF2-driven response enhances chemoresistance and promotes tumor cell migration, two hallmarks of aggressive cancer. Therapeutically, we demonstrate that pharmacological inhibition of the glyoxalase system—the major pathway for MGO detoxification—restores drug sensitivity in patient-derived cells and xenograft models, revealing a context-dependent metabolic vulnerability in AKR1A1 loss conditions. These findings identify AKR1A1 as a metabolic tumor suppressor and uncover crosstalk between S-nitrosylation and glycation as a key regulatory axis linking metabolic reprogramming to NRF2-driven therapy resistance, offering glyoxalase inhibition as a potential precision treatment strategy for RCC and HCC. Aldo-ketoreductase 1A1 (AKR1A1), a detoxifying enzyme, is reported to have an alternative role in regulating S-nitrosylation. Here, the authors show that AKR1A1 regulates S-nitrosylation of PKM2, and its loss leads to metabolic changes that promote chemoresistance and cell migration in liver and renal cancers.
Source: Nature Communications
Authors: Chiara Pecorari, Mojca Bratina, Evelyn Gonzalez, Salvatore Rizza, Letizia Incampo, Lina Vardouli, Paola Giglio, Elena Maresca, Zsófia Márta Sztupinszki, Marcus Montanares Kildegaard Nielsen, Perrine Verdys, Mario Presti, Maria Pires Pacheco, Yuya Qiu, Samuel D. Mador, Trine Skov Petersen, Julie Lund Petersen, Yonglun Luo, Emmanuelle Bignon, Zoltan Szallasi, Marco Donia, Jonathan S. Stamler, Simone Cardaci, Thomas Sauter, Giuseppe Filomeni
Institutions: University of Luxembourg, Boston Children's Hospital, Roskilde University, Herlev Hospital, Copenhagen University Hospital, Centre National de la Recherche Scientifique, Laboratoire de Physique et Chimie Théoriques, Université de Lorraine, Aarhus University, Aarhus University Hospital, Steno Diabetes Center Aarhus, Semmelweis University, University Hospitals Cleveland Medical Center, Case Western Reserve University, IRCCS Ospedale San Raffaele, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, University of Rome Tor Vergata
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Breast Cancer Research Foundation, Kræftens Bekæmpelse, European Commission, Fonds National de la Recherche Luxembourg, Ministero dell’Istruzione, dell’Università e della Ricerca, Lundbeckfonden, Novo Nordisk, Associazione Italiana per la Ricerca sul Cancro, Syddansk Universitet, Novo Nordisk Fonden, H. Lundbeck A/S, HORIZON EUROPE Framework Programme, NextGenerationEU
OpenAlex ID: W7203820003