{"doi":"10.1101/2025.05.13.653579","title":"Inhibition of NF-κB Signaling by the Reactive Glycolytic Metabolite Methylglyoxal","abstract":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":566059,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9605,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1469520,"name":"Woojin Choi","orcid":"0000-0002-3591-8036","position":1,"is_corresponding":false},{"id":141781,"name":"R. Luke Wiseman","orcid":"0000-0001-9287-6840","position":2,"is_corresponding":false},{"id":310926,"name":"Michael J. Bollong","orcid":"0000-0001-9439-1476","position":3,"is_corresponding":false},{"id":712062,"name":"Caroline Stanton","orcid":"0000-0001-5786-6671","position":0,"is_corresponding":true}],"reference_count":28,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:56:32.546082Z","pmid":"40463275","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}