Stanton Caroline, Choi Woojin, Wiseman R Luke, Bollong Michael J
Department of Chemistry, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
bioRxiv. 2025 May 16:2025.05.13.653579. doi: 10.1101/2025.05.13.653579.
The NF-κB 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-κB 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-κB signaling, decreasing transcriptional output in response to several canonical NF-κB activating stimuli. Mechanistically, PGK1 inhibition promotes the accumulation of the glycolytic metabolite methylglyoxal, which crosslinks and inactivates NF-κB 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.
转录因子复合物的NF-κB家族是炎症的核心调节因子，其失调会导致多种炎症性疾病的病理变化。因此，确定抑制NF-κB过度激活的药理机制仍然是一个至关重要的领域。在这里，我们证明用小分子抑制剂CBR-470-2抑制糖酵解酶磷酸甘油酸激酶1（PGK1）会导致NF-κB信号减弱，减少对几种经典NF-κB激活刺激的转录输出。从机制上讲，PGK1抑制促进糖酵解代谢物甲基乙二醛的积累，甲基乙二醛会交联并使NF-κB蛋白失活，限制这些转录因子复合物的磷酸化和核转位。这项工作建立了中心碳代谢与免疫信号之间的关键联系，并进一步支持了PGK1抑制可能是增加细胞存活率和减轻疾病炎症的可行策略这一观点。
