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Immunol."],"abstract":"<jats:p>Aquaporin-4 immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disease (NMOSD) is an autoimmune astrocytopathy in which a single attack may cause permanent visual or neurological disability. Although targeted immunotherapies reduce relapse risk, they do not establish repair of previously injured tissue. Repair failure is framed as disruption of an astrocyte-organized environment required for glial communication, oligodendrocyte lineage progression, myelin formation, and axonal survival. Five linked barriers organize the review: loss of astrocytic homeostatic support, glial uncoupling, oligodendrocyte precursor cell maturation stall, depletion of repairable substrate, and failure to transition from injury resolution to active repair. Human pathology and experimental studies show that astrocyte survival, repopulation, or barrier resealing does not necessarily restore the functions required for remyelination. Microglia and macrophages, peripheral immune activity, organelle and metabolic stress, and the neurovascular and extracellular matrix environment further modify repair capacity. Delayed-treatment studies of clobetasol and edaravone provide the strongest disease-relevant preclinical evidence that myelin recovery can be enhanced after demyelination has developed, whereas most other strategies remain indirect or repair-permissive. These findings do not establish human efficacy; a human remyelination claim would require convergent evidence of new myelin, improved conduction, and durable regional benefit. Priorities include disease-specific delayed-treatment models, direct confirmation of newly formed myelin, and testing under persistent AQP4-IgG-related injury. As of 24 August 2026, no controlled human study has demonstrated remyelination of an established AQP4-IgG-positive NMOSD lesion.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1889927","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:15:20Z","timestamp":1790680520000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Why repair fails in AQP4-IgG-positive neuromyelitis optica spectrum disease: an astrocyte-centered framework for remyelination and neuroaxonal preservation"],"prefix":"10.3389","volume":"17","author":[{"given":"Wenjing","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Neurology, The First Affiliated Hospital of Guangxi Medical University","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ni","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The First Affiliated 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