Exogenous pyruvate is therapeutic against colitis by targeting cytosolic phospholipase A2
Ulcerative colitis is an idiopathic, chronic inflammatory bowel disease. Its pathogenesis is multifactorial involving inflammation and immune dysregulation. Proinflammatory TNFα/NFκB signaling is believed to play a cardinal role in ulcerative colitis. Growing evidence indicates the molecular interac...
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KeAi Communications Co., Ltd.
2025-09-01
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| Series: | Genes and Diseases |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352304225000601 |
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| author | Sadaf Hasan Nabil Ghani Xiangli Zhao Julia Good Chuan-ju Liu |
| author_facet | Sadaf Hasan Nabil Ghani Xiangli Zhao Julia Good Chuan-ju Liu |
| author_sort | Sadaf Hasan |
| collection | DOAJ |
| description | Ulcerative colitis is an idiopathic, chronic inflammatory bowel disease. Its pathogenesis is multifactorial involving inflammation and immune dysregulation. Proinflammatory TNFα/NFκB signaling is believed to play a cardinal role in ulcerative colitis. Growing evidence indicates the molecular interactions between the cellular metabolites and different phases of inflammation. This study aims to identify the metabolites that can inhibit TNFα/NFκB signaling and are potentially therapeutic against various TNFα-associated inflammatory diseases, particularly inflammatory bowel diseases. We performed in vitro and in vivo screening of cellular metabolites to inhibit TNFα/NFκB signaling. Multiple confirmation assays, including NFκB translocation, quantitative real-time PCR, ELISA, immunofluorescence staining, and RNA sequencing analysis were executed. Drug affinity-responsive target stability assay with proteomics was utilized for target identification. cPLA2 ablated mice with dextran sodium sulfate-induced colitis were employed to assess pyruvate's dependence on its molecular target in attenuating ulcerative colitis pathogenesis. Metabolite screening and subsequent validation with multiple approaches led to the isolation of pyruvate, a glycolytic metabolite, and a critical node in several metabolic pathways, as a novel inhibitor of TNFα/NFκB signaling. Importantly, pyruvate suppressed inflammation, preserved colonic histology, maintained tight junction proteins, and regulated permeability in the ulcerative colitis model. Additionally, cPLA2 was identified as a previously unknown target of pyruvate and pyruvate largely lost its therapeutic effects against ulcerative colitis in cPLA2-deficient mice. Conclusively, this study not only unveils pyruvate as an antagonist of TNFα/NFκB signaling and therapeutic intervention against colitis but also provides mechanistic insight into the mode of action of pyruvate. |
| format | Article |
| id | doaj-art-81bbbb51bd1842f58e217b7704ce7291 |
| institution | DOAJ |
| issn | 2352-3042 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Genes and Diseases |
| spelling | doaj-art-81bbbb51bd1842f58e217b7704ce72912025-08-20T03:15:02ZengKeAi Communications Co., Ltd.Genes and Diseases2352-30422025-09-0112510157110.1016/j.gendis.2025.101571Exogenous pyruvate is therapeutic against colitis by targeting cytosolic phospholipase A2Sadaf Hasan0Nabil Ghani1Xiangli Zhao2Julia Good3Chuan-ju Liu4Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, NY 10010, USADepartment of Medicine, Division of Internal Medicine, Saint Peter's University Hospital, Rutgers University, New Brunswick, NJ 08901, USADepartment of Orthopedic Surgery, New York University Grossman School of Medicine, New York, NY 10010, USA; Department of Orthopedics & Rehabilitation, Yale School of Medicine, New Haven, CT 06510, USADepartment of Orthopedic Surgery, New York University Grossman School of Medicine, New York, NY 10010, USADepartment of Orthopedic Surgery, New York University Grossman School of Medicine, New York, NY 10010, USA; Department of Cell Biology, New York University Grossman School of Medicine, New York, NY 10010, USA; Department of Orthopedics & Rehabilitation, Yale School of Medicine, New Haven, CT 06510, USA; Corresponding author. Department of Orthopedics & Rehabilitation, Yale School of Medicine, New Haven, CT06510, USA. Tel.: 203-785-5968.Ulcerative colitis is an idiopathic, chronic inflammatory bowel disease. Its pathogenesis is multifactorial involving inflammation and immune dysregulation. Proinflammatory TNFα/NFκB signaling is believed to play a cardinal role in ulcerative colitis. Growing evidence indicates the molecular interactions between the cellular metabolites and different phases of inflammation. This study aims to identify the metabolites that can inhibit TNFα/NFκB signaling and are potentially therapeutic against various TNFα-associated inflammatory diseases, particularly inflammatory bowel diseases. We performed in vitro and in vivo screening of cellular metabolites to inhibit TNFα/NFκB signaling. Multiple confirmation assays, including NFκB translocation, quantitative real-time PCR, ELISA, immunofluorescence staining, and RNA sequencing analysis were executed. Drug affinity-responsive target stability assay with proteomics was utilized for target identification. cPLA2 ablated mice with dextran sodium sulfate-induced colitis were employed to assess pyruvate's dependence on its molecular target in attenuating ulcerative colitis pathogenesis. Metabolite screening and subsequent validation with multiple approaches led to the isolation of pyruvate, a glycolytic metabolite, and a critical node in several metabolic pathways, as a novel inhibitor of TNFα/NFκB signaling. Importantly, pyruvate suppressed inflammation, preserved colonic histology, maintained tight junction proteins, and regulated permeability in the ulcerative colitis model. Additionally, cPLA2 was identified as a previously unknown target of pyruvate and pyruvate largely lost its therapeutic effects against ulcerative colitis in cPLA2-deficient mice. Conclusively, this study not only unveils pyruvate as an antagonist of TNFα/NFκB signaling and therapeutic intervention against colitis but also provides mechanistic insight into the mode of action of pyruvate.http://www.sciencedirect.com/science/article/pii/S2352304225000601ColitisCytosolic phospholipase A2Drug affinity-responsive target stability assayInflammationPyruvateTNFα/NFκB signaling |
| spellingShingle | Sadaf Hasan Nabil Ghani Xiangli Zhao Julia Good Chuan-ju Liu Exogenous pyruvate is therapeutic against colitis by targeting cytosolic phospholipase A2 Genes and Diseases Colitis Cytosolic phospholipase A2 Drug affinity-responsive target stability assay Inflammation Pyruvate TNFα/NFκB signaling |
| title | Exogenous pyruvate is therapeutic against colitis by targeting cytosolic phospholipase A2 |
| title_full | Exogenous pyruvate is therapeutic against colitis by targeting cytosolic phospholipase A2 |
| title_fullStr | Exogenous pyruvate is therapeutic against colitis by targeting cytosolic phospholipase A2 |
| title_full_unstemmed | Exogenous pyruvate is therapeutic against colitis by targeting cytosolic phospholipase A2 |
| title_short | Exogenous pyruvate is therapeutic against colitis by targeting cytosolic phospholipase A2 |
| title_sort | exogenous pyruvate is therapeutic against colitis by targeting cytosolic phospholipase a2 |
| topic | Colitis Cytosolic phospholipase A2 Drug affinity-responsive target stability assay Inflammation Pyruvate TNFα/NFκB signaling |
| url | http://www.sciencedirect.com/science/article/pii/S2352304225000601 |
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