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bioRxiv · 10.1101/2025.05.13.653579

Inhibition of NF-κB Signaling by the Reactive Glycolytic Metabolite Methylglyoxal

Stanton, C.·Choi, W.·Wiseman, L.·Bollong, M. J.
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Abstract

The NF-{kappa}B family of transcription factor complexes are central regulators of inflammation, and their dysregulation contributes to the pathology of multiple inflammatory disease conditions. Accordingly, identifying pharmacological mechanisms that restrain NF-{kappa}B overactivation remains an area of key importance. Here, we demonstrate that inhibition of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) with the small molecule inhibitor CBR-470-2 results in attenuated NF-{kappa}B signaling, decreasing transcriptional output in response to several canonical NF-{kappa}B activating stimuli. Mechanistically, PGK1 inhibition promotes the accumulation of the glycolytic metabolite methylglyoxal, which crosslinks and inactivates NF-{kappa}B proteins, limiting the phosphorylation and nuclear translocation of these transcription factor complexes. This work establishes a key connection between central carbon metabolism and immune signaling and further supports the notion that PGK1 inhibition may be a viable strategy to increase cellular survival and dampen inflammation in disease.

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Stanton, C., Choi, W., Wiseman, L., Bollong, M. J.. 2025-05-16. Inhibition of NF-κB Signaling by the Reactive Glycolytic Metabolite Methylglyoxal. https://doi.org/10.1101/2025.05.13.653579

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