ArticleProceedings of the National Academy of Sciences of the United States of America2023
S-lactoyl modification of KEAP1 by a reactive glycolytic metabolite activates NRF2 signaling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 39 citations in OpenAlex.
- Bone marrow stromal cells promote chemoresistance in acute myeloid leukaemia through P2RX7-mediated antioxidant defence.Experimental & molecular medicine · 2026Article
- Crosstalk between S-nitrosylation and glycation defines a metabolic vulnerability in liver and renal cancers.Nature communications · 2026Article
- Nrf2-mediated metabolic reprogramming drives regulatory T cell accumulation in hepatocellular carcinoma.Nature communications · 2026Article
- Lactate as a Chemical Modification on Proteins and Metabolites.Annual review of biochemistry · 2026Review
- Covalent Modification of Keap1 by the Key Metabolic Cofactor Coenzyme A Under Oxidative and Metabolic Stress.Antioxidants (Basel, Switzerland) · 2026Article
- The Role and Mechanism of Nrf2 in Ameliorating Oxidative Stress and Inflammation in IR Mice by Aerobic Exercise.International journal of molecular sciences · 2026Article
- Lactylation-regulated ferroptosis: mechanisms, disease associations, and therapeutic strategies.Archives of pharmacal research · 2026Review
- Lactylation and targeted therapy resistance in hepatocellular carcinoma.Clinical epigenetics · 2026Review
- Context-dependent NRF2 signaling in cancer: mechanisms and precision modulation.Molecular biology reports · 2026Review
- Apigenin combined with aerobic exercise alleviates oxidative stress and inflammation in high-fat diet-induced NAFLD mice by modulating the Keap1/Nrf2/ARE pathway.Scientific reports · 2026Article
- Discovery of metabolites produced by reactions between central carbon metabolites and cysteine that mark inflammatory macrophages.bioRxiv : the preprint server for biology · 2026Article
- Metabolite-driven protein modifications in immune signaling: from established principles to emerging pyruvylation.Frontiers in immunology · 2026Review
- Regulation of drug resistance in bladder urothelial carcinoma by tumor aerobic glycolysis.Journal of translational medicine · 2025Review
- Article
- Cysteine S-acetylation is a widespread post-translational modification on metabolic proteins.npj metabolic health and disease · 2025Article
- Nrf2 Drives Epigenetic Reprogramming and Acts as the Master Regulator of KLF4 Expression and Activity in Arsenic-Induced Transformation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Reactivity-based metabolomics reveal cysteine has glyoxalase 1-like and glyoxalase 2-like activities.Nature chemical biology · 2025Article
- Roles of lactylation in lipid metabolism and related diseases.Cell death discovery · 2025Review
- Post-translational modifications of cancer immune checkpoints: mechanisms and therapeutic strategies.Molecular cancer · 2025Review
- PP1A Modulates the Efficacy of Lenvatinib Plus ICIs Therapy by Inhibiting Ferroptosis in Hepatocellular Carcinoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
Corrections and comments
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Authors and funding
15 authors at 2 institutions in 1 country.
Funding
Abstract
KEAP1 (Kelch-like ECH-associated protein), a cytoplasmic repressor of the oxidative stress responsive transcription factor Nuclear factor erythroid 2-related factor 2 (NRF2), senses the presence of electrophilic agents by modification of its sensor cysteine residues. In addition to xenobiotics, several reactive metabolites have been shown to covalently modify key cysteines on KEAP1, although the full repertoire of these molecules and their respective modifications remain undefined. Here, we report the discovery of sAKZ692, a small molecule identified by high-throughput screening that stimulates NRF2 transcriptional activity in cells by inhibiting the glycolytic enzyme pyruvate kinase. sAKZ692 treatment promotes the buildup of glyceraldehyde 3-phosphate, a metabolite which leads to S-lactate modification of cysteine sensor residues of KEAP1, resulting in NRF2-dependent transcription. This work identifies a posttranslational modification of cysteine derived from a reactive central carbon metabolite and helps further define the complex relationship between metabolism and the oxidative stress-sensing machinery of the cell.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.