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

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.