{ "abstract": "Exercise can enhance the body’s ability to resist infections, but its molecular mechanisms are still unclear. Here, we found that exercise can induce a hyperactivation-like state of the NLRP3 inflammasome during infection, which enhances the body’s ability to resist infection by continuously secreting inflammatory cytokines and reducing immune cell pyroptosis. At the molecular level, exercise enhances the binding between CNDP2 and GSDMD, promoting the production of γ-Glu-Cys. γ-Glu-Cys binds to CypD and inhibits the binding between CypD and GSDMD, thereby avoiding further damage to the mitochondrial inner membrane during the occurrence of inflammasomes. Limited mitochondrial DNA leakage allows the NLRP3 inflammasome to a hyperactivate state. Our findings reveal the molecular mechanisms by which exercise enhances the body’s ability to resist infections, and provide possible standards for better guiding exercise intensity to improve anti-infection capabilities in the future. Author summary: Exercise triggers the production of numerous metabolites. Here, we discovered that exercise promotes the binding between CNDP2 and GSDMD in macrophages, leading to the generation of γ-Glu-Cys. During inflammasome activation, γ-Glu-Cys binds to mitochondrial CypD and prevents it from interacting with the GSDMD N-terminus. This restricts excessive permeabilization of the mitochondrial inner membrane, resulting in a controlled, limited release of mitochondrial DNA. Rather than suppressing the inflammasome, this controlled mitochondrial signal shifts the response into a hyperactivation-like state, characterized by sustained IL-1β secretion without rapid cell lysis. Consequently, exercise-trained macrophages exhibit prolonged and enhanced anti-infection activity. Our work identifies γ-Glu-Cys as an exercise-induced metabolite, providing a mechanistic explanation for why moderate exercise is beneficial for host defense against infections. These insights may open new avenues for developing immunomodulatory strategies that mimic the beneficial effects of exercise.", "abstract_shown": true, "affiliations": [ "Beijing Life Science Academy, Beijing, China", "Department of Immunology, School of Basic Medical Sciences, State Key Laboratory of Molecular Oncology, Peking University, Beijing, China", "Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing, China", "Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China", "Department of Sports Medicine, Peking University Third Hospital, Beijing, China", "Beijing Key Laboratory of Sports Injuries, Institute of Sports Medicine of Peking University, Beijing, China", "Department of Laboratory Medicine, Beijing Hospital, National Center for Gerontology, National Clinical Research Center for Gerontology, The Key Laboratory of Geriatrics of NHC, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China", "CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China" ], "article_type": "Research Article", "arxiv": null, "author_total": 12, "authors": [ { "affs": [ 0 ], "name": "Yan Qian" }, { "affs": [ 1 ], "name": "Xiangyun Cheng" }, { "affs": [ 2 ], "name": "Qiannv Liu" }, { "affs": [ 3 ], "name": "Chunlei Wang" }, { "affs": [ 4 ], "name": "Chun Kong" }, { "affs": [ 5 ], "name": "Mengqian Li" }, { "affs": [ 6 ], "name": "Xiangyang Geng" }, { "affs": [ 7 ], "name": "Liya Ai" }, { "name": "Mindi Zhao" }, { "name": "Shuo Wang" }, { "name": "Dong Jiang" }, { "name": "Pengyan Xia" } ], "bibtex": "https://research.draconitic.com/paper/dv6g6jvxk9me9.bib", "cited_by": 0, "doi": "10.1371/journal.ppat.1014554", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014554", "id": "dv6g6jvxk9me9", "issns": [ "1553-7374" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014554", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "1312|Inflammasome and immune disorders" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Immune system proteins/Antibodies" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Immune system proteins/Inflammasomes" ], [ "plos", "/Biology and life sciences/Bioengineering/Biotechnology/Genetic engineering/Genetically modified organisms/Genetically modified animals" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Immunology/Immune system proteins/Antibodies" ], [ "plos", "/Biology and life sciences/Immunology/Immune system proteins/Inflammasomes" ], [ "plos", "/Biology and life sciences/Physiology/Immune physiology/Antibodies" ], [ "plos", "/Biology and life sciences/Psychology/Behavior/Sedentary behavior" ], [ "plos", "/Engineering and technology/Bioengineering/Biotechnology/Genetic engineering/Genetically modified organisms/Genetically modified animals" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells/White blood cells/Macrophages" ], [ "plos", "/Medicine and health sciences/Immunology/Immune system proteins/Antibodies" ], [ "plos", "/Medicine and health sciences/Immunology/Immune system proteins/Inflammasomes" ], [ "plos", "/Research and analysis methods/Biological cultures/Cell cultures" ], [ "plos", "/Research and analysis methods/Immunologic techniques/Immunoassays/Enzyme-linked immunoassays" ], [ "plos", "/Research and analysis methods/Precipitation techniques/Immunoprecipitation" ], [ "plos", "/Social sciences/Psychology/Behavior/Sedentary behavior" ] ], "openalex": "W7221147840", "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014554&type=printable", "pmcid": null, "pmid": null, "published": "2026-10-09", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/dv6g6jvxk9me9.ris", "sources": [ { "first_seen": "2026-10-30T12:17:30Z", "native_id": "10.1371/journal.ppat.1014554", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014554" } ], "subjects": [ { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" } ], "title": "Exercise promotes host anti-infection activity through CNDP2 metabolite-mediated inflammasome hyperactivation", "title_text": "Exercise promotes host anti-infection activity through CNDP2 metabolite-mediated inflammasome hyperactivation", "type": "peer-reviewed", "updated_at": "2026-10-30T12:17:30Z", "url": "https://research.draconitic.com/paper/dv6g6jvxk9me9", "venue": "PLOS Pathogens", "versions": [] }