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Here we identified SHIP1 as a regulator of endo-lysosomal homeostasis in human microglia.\n                  <jats:italic>INPP5D<\/jats:italic>\n                  haploinsufficiency impaired endosome maturation and lysosomal degradation, leading to lipid droplet accumulation, lysosomal stress, and NLRP3 inflammasome activation. SHIP1-deficient microglia shifted from an immune-responsive state toward a disease-associated state with elevated cargo-selective phagocytosis. Although amyloid-\u03b2 uptake was unaffected, SHIP1-deficient microglia accumulated intracellular amyloid-\u03b2 and exhibited exacerbated lipid droplet accumulation, consistent with defective lysosomal processing. Proteomic analysis of genetically diverse human microglia revealed that the protective\n                  <jats:italic>INPP5D<\/jats:italic>\n                  rs10933431 variant is associated with elevated phosphatase-domain containing SHIP1, and protein profiles consistent with enhanced endolysosomal trafficking. In mice xenografted with SHIP1-deficient human microglia, high amyloid-\u03b2 burden exacerbated lysosomal, lipid droplet and inflammasome phenotypes. Together, these findings identify disrupted endo-lysosomal trafficking and degradative capacity as mechanisms linking\n                  <jats:italic>INPP5D<\/jats:italic>\n                  dysfunction to disease-associated microglial states in AD.\n                <\/jats:p>","DOI":"10.1101\/2025.10.27.684632","type":"posted-content","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T04:40:17Z","timestamp":1761626417000},"source":"Crossref","is-referenced-by-count":5,"title":["INPP5D\/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4735-6322","authenticated-orcid":false,"given":"Gizem","family":"Terzioglu","sequence":"first","affiliation":[{"name":"Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA, 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