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M\u00fcller glial cells, which maintain retinal water\u2013ion homeostasis through AQP4 and Kir4.1 channels, may represent a primary retinal target of circulating NMOSD-related autoantibodies and serum factors. We investigated how sera from AQP4-IgG+, MOG-IgG+, and double-seronegative (DSN) NMOSD patients affect the expression and localization of key M\u00fcller cell biomarkers. Human MIO-M1 M\u00fcller cells were stimulated with complement-inactivated patient or healthy control sera, and protein\/mRNA levels of AQP4, Kir4.1, CRALBP, VEGF, and IL-6 were evaluated using immunofluorescence, Western blotting, and RT-qPCR. AQP4 membrane localization and internalization were assessed using WGA and EEA1 colocalization analyses. AQP4-IgG+\u2009sera uniquely induced a marked reduction in AQP4 and Kir4.1 protein expression, together with mild AQP4 internalization and reduced membrane association. Despite protein loss, AQP4 and Kir4.1 transcripts were significantly upregulated, indicating a compensatory transcriptional response to antibody-mediated depletion. MOG-IgG\u2009+\u2009sera produced no major changes in the examined markers. In contrast, DSN sera selectively increased VEGF expression at both protein and mRNA levels, suggesting an alternative, antibody-independent mechanism of M\u00fcller cell activation. IL-6 expression showed non-significant changes across groups. These findings demonstrate subgroup-specific retinal glial responses to patient sera, with AQP4-IgG mediating early complement-independent loss of the AQP4\u2013Kir4.1 water\u2013ion channel complex, and DSN sera engaging distinct VEGF-related pathways. Our study establishes M\u00fcller cells as active contributors to NMOSD-associated retinal pathology and provides a foundation for exploring subgroup-tailored changes.<\/jats:p>","DOI":"10.1007\/s12035-026-05892-y","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T05:26:28Z","timestamp":1777872388000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Molecular Mechanisms of Retinal Damage in NMOSD via M\u00fcller Glial Cell Stimulation with Patient Sera"],"prefix":"10.1007","volume":"63","author":[{"given":"Sahra","family":"Kabiri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0130rfan Burak","family":"G\u00f6lo\u011flu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmetcan","family":"Sezen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ceren","family":"Tuncer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Haroon","family":"Qureshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rabia G\u00f6k\u00e7en G\u00f6z\u00fcbatik","family":"\u00c7elik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afsun","family":"\u015eahin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8524-5087","authenticated-orcid":false,"given":"Ay\u015fe","family":"Alt\u0131nta\u015f","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"issue":"2","key":"5892_CR1","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1212\/WNL.0000000000001729","volume":"85","author":"DM Wingerchuk","year":"2015","unstructured":"Wingerchuk DM et al (2015) International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. 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