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Transglutaminase 2 (TGM2), a multifunctional enzyme implicated in neuroinflammation and extracellular matrix remodeling, remains underexplored in TBI\u2010related BBB dysfunction. This study elucidates the role of TGM2 in BBB disruption following TBI and explores its therapeutic potential in mitigating BBB damage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The controlled cortical impact (CCI) and oxygen\u2013glucose deprivation (OGD) models were used to establish in\u00a0vivo and in\u00a0vitro TBI models in mice. The experimental approaches comprised RNA sequencing, Western blot analysis, RT\u2010qPCR, immunofluorescence staining, and behavioral assessments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>TGM2 expression peaked at 48\u2009h after TBI, predominantly in brain endothelial cells, correlating with BBB disruption (reduced tight junction proteins, increased edema). TGM2 knockdown may attenuate MMP\u20109 via the IL\u201017 pathway, restoring BBB integrity. In\u00a0vivo, TGM2 inhibition reduced Evans blue leakage, upregulated CLAUDIN\u20105\/ZO\u20101, and improved motor coordination, balance, and spatial memory.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>TGM2 is a key molecule affecting the BBB after TBI. Inhibition of TGM2 can alleviate the blood\u2013brain barrier and neurological deficits after TBI, acting through the IL\u201017\u2010MMP\u20109 axis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.70887","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T04:49:46Z","timestamp":1776660586000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Inhibition of Transglutaminase 2 Preserves Blood\u2013Brain Barrier Integrity and Improves Neurological Outcomes After Experimental Traumatic Brain Injury in Mice"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7243-0358","authenticated-orcid":false,"given":"Jieru","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, the Affiliated Hospital Southwest Medical University  Luzhou China"},{"name":"Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital Southwest Medical University  Luzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, the Affiliated Hospital Southwest Medical University  Luzhou China"},{"name":"Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital Southwest Medical University  Luzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6821-8167","authenticated-orcid":false,"given":"Xiancheng","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, the Affiliated Hospital Southwest Medical University  Luzhou China"},{"name":"Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital Southwest Medical University  Luzhou 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