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Although oligodendrocyte dysfunction is common in the central nervous system (CNS), how these cells respond to injury remains incompletely understood. Here we show, using mouse models and mouse tissue analyses, that OLs respond to demyelinating diseases by increasing the expression and secretion of serine protease inhibitor clade A member 3N (SERPINA3N). This transition of homeostatic OLs to Serpina3n-expressing OLs (SerpinOLs) occurs not only in demyelinating disease, but also after stroke, endotoxin-induced injury, neurodegeneration, traumatic injury, and healthy aging. Mechanistically, direct injury to OLs, rather than inflammation alone, drives the transition. Phenotypically, SerpinOLs show inflammatory and immune-regulatory features and activation of signal transducer and activator of transcription 3 (STAT3), which is required for SERPINA3N induction. Functionally, SerpinOLs amplify neuroinflammation and glial activation toward pro-inflammatory and neurodegenerative states. Together, SerpinOLs represent a common population of injury-transduced OLs that contributes to CNS pathology beyond myelin production.<\/jats:p>","DOI":"10.1038\/s41467-026-76159-2","type":"journal-article","created":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T04:20:11Z","timestamp":1787977211000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Injury-transduced oligodendrocytes modulate neuroinflammation and glial activation in diseased and non-diseased central nervous system"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7744-4078","authenticated-orcid":false,"given":"Yan","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meina","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joohyun","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Kyu","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3814-2509","authenticated-orcid":false,"given":"Bo","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7791-1342","authenticated-orcid":false,"given":"Shinghua","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wensheng","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3410-8389","authenticated-orcid":false,"given":"Fuzheng","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,29]]},"reference":[{"key":"76159_CR1","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1016\/j.devcel.2015.01.016","volume":"32","author":"KK Bercury","year":"2015","unstructured":"Bercury, K. 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