{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:18:08Z","timestamp":1791919088272,"version":"4.3.4"},"reference-count":63,"publisher":"American Association for the Advancement of Science (AAAS)","funder":[{"name":"Natural Science Youth Foundation of Hebei Province","award":["H2024206108"],"award-info":[{"award-number":["H2024206108"]}]},{"name":"Beijing-Tianjin-Hebei Collaborative Innovation Community Construction Project","award":["22347702D"],"award-info":[{"award-number":["22347702D"]}]},{"name":"central government guides local funds for science and technology development","award":["246Z7709G"],"award-info":[{"award-number":["246Z7709G"]}]},{"name":"Innovative Experiment Project for College Students of Hebei Medical University","award":["CXSY2025012"],"award-info":[{"award-number":["CXSY2025012"]}]}],"content-domain":{"domain":["spj.science.org"],"crossmark-restriction":true},"short-container-title":["Research"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:p>\n                    Sepsis remains a leading global cause of death, with immune heterogeneity\u2019s molecular mechanisms poorly understood. This study analyzed 1,862 human peripheral blood samples, constructing a molecular interaction disturbance network that first revealed the network biology underlying sepsis immune heterogeneity. We identified 3 sepsis subtypes with marked different prognostic characteristics, with the C1 subtype showing the worst prognosis characterized by severe CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell exhaustion\u2014validated across 10 independent cohorts. Integrating single-cell transcriptomics from over 450,000 cells, proteomics, and functional validation, we identified monocyte-derived matrix metalloproteinase-9 (MMP9) as a key regulator driving CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell dysfunction. Mechanistically, MMP9 modulates T cell exhaustion through dual mechanisms: promoting leukocyte-associated immunoglobulin-like receptor-1 (Lair-1) aggregation on T cell membranes, directly inhibiting zeta chain of T cell receptor associated protein kinase 70 (ZAP70) phosphorylation in T cell receptor signaling, while impairing Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -release-activated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channel function and intracellular calcium clearance, causing calcium dysregulation that blocks nuclear factor of activated T cells (NFAT) activation and nuclear translocation. The selective MMP9 inhibitor MMP9-in-1 effectively reversed T cell dysfunction, restored calcium homeostasis and NFAT nuclear translocation, markedly enhanced CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell interleukin-2 and interferon-\u03b3 production, and reduced programmed cell death protein 1 expression. This work establishes a comprehensive translational framework from molecular network disturbances to clinical phenotypes, advancing sepsis immunopathophysiology understanding and providing effective targets for the treatment of sepsis patients.\n                  <\/jats:p>","DOI":"10.34133\/research.0996","type":"journal-article","created":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T23:07:14Z","timestamp":1762124834000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":12,"title":["Targeting Matrix Metalloproteinase-9 to Alleviate T Cell Exhaustion and Improve Sepsis Prognosis"],"prefix":"10.34133","volume":"8","author":[{"given":"Xuan","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Department of Immunology, \rHebei Medical University, Shijiazhuang, PR China."},{"name":"Diagnostic Center of Infections, \rThe Second Hospital of Hebei Medical University, Shijiazhuang, PR China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyuan","family":"Ning","sequence":"additional","affiliation":[{"name":"Chinese Academy of Medical Sciences & Peking Union Medical College","place":["PR China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine, \rThe Second Hospital of Hebei Medical University, Shijiazhuang, PR China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongru","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Department of Immunology, \rHebei Medical University, Shijiazhuang, PR China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlei","family":"Cui","sequence":"additional","affiliation":[{"name":"Key Laboratory of Immune 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