{
  "abstract": "Background: The development of {beta}-amyloid (A{beta}) pathology in Alzheimer's disease (AD) is accompanied by profound changes in astrocytes and microglia and associated neuroinflammation. Soluble epoxide hydrolase (sEH), which degrades anti-inflammatory epoxyeicosatrienoic acids (EETs), is elevated in the AD brain, yet how EETs restrain inflammation remains poorly understood. Methods: We performed single-nucleus RNA sequencing (snRNA-seq) on brains from wild-type, sEH knockout, 5xFAD, and 5xFAD; sEH knockout mice, and used primary mouse microglia and human induced pluripotent stem cell (iPSC)-derived microglia to define the underlying mechanism. To test cell-type-specific contributions, we generated astrocyte- and endothelial-specific she knockout mice and crossed them with 5xFAD mice. Results: Genetic disruption of sEH in 5xFAD mice markedly reduced the abundance of a type I interferon (IFN)-responsive microglial subcluster and lowered phospho-STING (pSTING) levels. In primary microglia, supplementation with 11,12-EET attenuated STING activation and IFN target gene expression; blocking lysosomal acidification abolished this effect and caused pSTING to accumulate, identifying lysosomal degradation as a critical route for terminating STING signaling. 11,12-EET also enhanced microglial lysosomal acidification and A{beta} phagocytosis. Astrocytic, but not endothelial, disruption of sEH recapitulated the reductions in A{beta} pathology and microglial STING activation seen in global sEH-deficient mice, identifying astrocytes as the major cellular source of EETs regulating this pathway. Conclusion: We define an astrocyte-microglia axis in which astrocytic sEH limits EET availability and thereby sustains microglial STING signaling. By promoting lysosomal clearance of pSTING, EETs suppress type I IFN signaling and enhance microglial A{beta} clearance, highlighting sEH inhibition as a therapeutic strategy targeting both neuroinflammation and lysosomal dysfunction in AD.",
  "abstract_shown": true,
  "affiliations": [
    "Baylor College of Medicine"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "name": "B. Ghosh"
    },
    {
      "name": "S. Wang"
    },
    {
      "name": "C. Qi"
    },
    {
      "name": "A. Ghosh"
    },
    {
      "name": "M. Comerota"
    },
    {
      "name": "C. S. Rajpurohit"
    },
    {
      "name": "D. C. Zeldin"
    },
    {
      "affs": [
        0
      ],
      "name": "H. Zheng"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2y18h9256734x.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.16.759679",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.16.759679v1.full",
  "id": "2y18h9256734x",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.16.759679v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "2808|Neuroinflammation and Neurodegeneration Mechanisms"
    ]
  ],
  "openalex": "W7223010027",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.16.759679v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-16",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/2y18h9256734x.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:28:41Z",
      "native_id": "10.64898/2026.10.16.759679",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.16.759679v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "Astrocytic sEH-EET signaling regulates microglial lysosomal function and suppresses the STING-Type I interferon pathway in Alzheimer's disease",
  "title_text": "Astrocytic sEH-EET signaling regulates microglial lysosomal function and suppresses the STING-Type I interferon pathway in Alzheimer's disease",
  "type": "preprint",
  "updated_at": "2026-10-30T12:28:41Z",
  "url": "https://research.draconitic.com/paper/2y18h9256734x",
  "venue": "bioRxiv",
  "versions": []
}