Crosstalk between S-nitrosylation and glycation defines a metabolic vulnerability in liver and renal cancers
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.
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BibTeX
@article{pecorari2026crosstalk,
title = {{Crosstalk between S-nitrosylation and glycation defines a metabolic vulnerability in liver and renal cancers}},
author = {Chiara Pecorari and Mojca Bratina and Evelyn Gonzalez and Salvatore Rizza and Letizia Incampo and Lina Vardouli and Paola Giglio and Elena Maresca and Zsófia Márta Sztupinszki and Marcus Montanares Kildegaard Nielsen and Perrine Verdys and Mario Presti and Maria Pires Pacheco and Yuya Qiu and Samuel Mador and Trine Skov Petersen and Julie Lund Petersen and Yonglun Luo and Emmanuelle Bignon and Zoltan Szallasi and Marco Donia and Jonathan Stamler and Simone Cardaci and Thomas Sauter and Giuseppe Filomeni},
journal = {Nature Communications},
year = {2026},
month = aug,
doi = {10.1038/s41467-026-76938-x},
url = {https://hal.science/hal-05756693v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Crosstalk between S-nitrosylation and glycation defines a metabolic vulnerability in liver and renal cancers
AU - Chiara Pecorari
AU - Mojca Bratina
AU - Evelyn Gonzalez
AU - Salvatore Rizza
AU - Letizia Incampo
AU - Lina Vardouli
AU - Paola Giglio
AU - Elena Maresca
AU - Zsófia Márta Sztupinszki
AU - Marcus Montanares Kildegaard Nielsen
AU - Perrine Verdys
AU - Mario Presti
AU - Maria Pires Pacheco
AU - Yuya Qiu
AU - Samuel Mador
AU - Trine Skov Petersen
AU - Julie Lund Petersen
AU - Yonglun Luo
AU - Emmanuelle Bignon
AU - Zoltan Szallasi
AU - Marco Donia
AU - Jonathan Stamler
AU - Simone Cardaci
AU - Thomas Sauter
AU - Giuseppe Filomeni
PY - 2026
DA - 2026/08/20
JO - Nature Communications
DO - 10.1038/s41467-026-76938-x
UR - https://hal.science/hal-05756693v1
AB - 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.
SN - 2041-1723
SN - 2041-1723
ER -