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The Hippo pathway kinases NDR1\/2 regulate macrophage function, but their role in microglia and DR remain unknown. This study investigates the function of the NDR2 kinase in microglial cells under high-glucose (HG) conditions. Using CRISPR-Cas9, we partially knocked out the Ndr2\/Stk38l gene in BV-2 mouse microglial cells and analyzed metabolic activity, phagocytosis, migration, and cytokine release. We confirmed NDR2 expression in microglia and observed increased levels under HG, suggesting a role in hyperglycemia-induced stress. Ndr2\/Stk38l (hereafter referred to as Ndr2) downregulation impaired mitochondrial respiration and reduced metabolic flexibility, indicating defective stress adaptation. Functionally, microglia with a partial downregulation of Ndr2 displayed reduced phagocytic and migratory capacity\u2014both dependent on cytoskeletal dynamics. Moreover, Ndr2 downregulation altered the secretory profile, elevating pro-inflammatory cytokines (IL-6, TNF, IL-17, IL-12p70) even under normal glucose levels. These findings identify NDR2 protein kinase as a key regulator of microglial metabolism and inflammatory behavior under diabetic conditions. By modulating immune and metabolic responses, NDR2 may contribute to the neuroinflammatory processes underlying DR. Targeting NDR2 function in microglia may offer novel therapeutic strategies to mitigate retinal inflammation and progression of DR.<\/jats:p>","DOI":"10.3390\/ijms262110630","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T13:15:14Z","timestamp":1762175714000},"page":"10630","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["NDR2 Kinase Regulates Microglial Metabolic Adaptation and Inflammatory Response: Critical Role in Glucose-Dependent Functional Plasticity"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2804-6342","authenticated-orcid":false,"given":"Beatriz","family":"Fazendeiro","sequence":"first","affiliation":[{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CiBB), University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Clinical Academic Centre of Coimbra (CACC), 3004-504 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9666-4594","authenticated-orcid":false,"given":"Ivo","family":"Machado","sequence":"additional","affiliation":[{"name":"Center for Innovative Biomedicine and Biotechnology (CiBB), University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Doctoral Program in Experimental Biology and Biomedicine (PDBEB), Institute of Interdisciplinary Research, University of Coimbra, 3004-504 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anabela","family":"Rolo","sequence":"additional","affiliation":[{"name":"Center for Innovative Biomedicine and Biotechnology (CiBB), University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Department of Life Sciences, University of Coimbra, 3030-790 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7519-1620","authenticated-orcid":false,"given":"Paulo","family":"Rodrigues Santos","sequence":"additional","affiliation":[{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CiBB), University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Clinical Academic Centre of Coimbra (CACC), 3004-504 Coimbra, Portugal"},{"name":"Laboratory of Immunology and Oncology, Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Institute of Immunology, Faculty of Medicine (FMUC), University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3001-301 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0477-1641","authenticated-orcid":false,"given":"Ant\u00f3nio Francisco","family":"Ambr\u00f3sio","sequence":"additional","affiliation":[{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CiBB), University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Clinical Academic Centre of Coimbra (CACC), 3004-504 Coimbra, Portugal"},{"name":"Association for Innovation and Biomedical Research on Light and Image (AIBILI), 3000-548 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2225-455X","authenticated-orcid":false,"given":"Paulo F.","family":"Santos","sequence":"additional","affiliation":[{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CiBB), University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Clinical Academic Centre of Coimbra (CACC), 3004-504 Coimbra, Portugal"},{"name":"Department of Life Sciences, University of Coimbra, 3030-790 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1116-8637","authenticated-orcid":false,"given":"H\u00e9l\u00e8ne","family":"L\u00e9ger","sequence":"additional","affiliation":[{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CiBB), University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Clinical Academic Centre of Coimbra (CACC), 3004-504 Coimbra, Portugal"},{"name":"Association for Innovation and Biomedical Research on Light and Image (AIBILI), 3000-548 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"ref_1","unstructured":"(2025, August 27). 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