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bioRxiv · 10.64898/2026.10.16.759679

Astrocytic sEH-EET signaling regulates microglial lysosomal function and suppresses the STING-Type I interferon pathway in Alzheimer's disease

Ghosh, B.·Wang, S.·Qi, C.·Ghosh, A.·Comerota, M.·Rajpurohit, C. S.·Zeldin, D. C.·Zheng, H.
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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.

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Ghosh, B., Wang, S., Qi, C., Ghosh, A., Comerota, M., Rajpurohit, C. S., Zeldin, D. C., Zheng, H.. 2026-10-20. Astrocytic sEH-EET signaling regulates microglial lysosomal function and suppresses the STING-Type I interferon pathway in Alzheimer's disease. https://doi.org/10.64898/2026.10.16.759679

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