Loss of the metabolic enzyme AKR1A1 in hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) creates a metabolic vulnerability that can be pharmacologically exploited to reverse drug resistance, according to a study published this week in Nature Communications. The work, led by Giuseppe Filomeni at the Danish Cancer Institute, identifies AKR1A1 as a metabolic tumor suppressor and links its loss to NRF2-mediated chemoresistance.
The researchers found that loss of AKR1A1 triggers S-nitrosylation of pyruvate kinase M2 (PKM2), inhibiting the enzyme and disrupting glycolysis. This causes accumulation of methylglyoxal (MGO), a toxic metabolic byproduct, which in turn promotes autophagic degradation of KEAP1. Loss of KEAP1 releases the transcription factor NRF2, activating a cellular stress-response program associated with chemoresistance and tumor cell migration.
The study links two forms of protein modification — nitric oxide-driven S-nitrosylation and MGO-driven glycation — in a metabolic signaling pathway that the authors said had not previously been characterized in this context. The causal role of PKM2 S-nitrosylation was supported by experiments showing that a mutant form of PKM2 resistant to the modification prevented MGO accumulation in AKR1A1-deficient cells.
Importantly, the resulting metabolic disruption creates a potential therapeutic vulnerability. AKR1A1-deficient cancer cells become increasingly dependent on the glyoxalase system, which detoxifies MGO and prevents it from reaching lethal concentrations. Pharmacologically inhibiting this pathway caused MGO to accumulate further and restored drug sensitivity, suggesting that AKR1A1 loss could serve as a biomarker for tumors susceptible to glyoxalase inhibition.
The findings were tested in engineered cancer cell lines, patient-derived HCC and RCC cells, and patient-derived xenograft models, providing evidence that the mechanism extends beyond conventional cell culture.