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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 CS, Zeldin DC, Zheng H.. bioRxiv, 2026-10-20
Topic: Inflammation, microglia and astrocytes
Background The development of β-amyloid (Aβ) 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 Aβ phagocytosis. Astrocytic, but not endothelial, disruption of sEH recapitulated the reductions in Aβ 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 Aβ clearance, highlighting sEH inhibition as a therapeutic strategy targeting both neuroinflammation and lysosomal dysfunction in AD.
Key findings
- 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.
Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record names 8 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Ghosh, B., Wang, S., Qi, C., Ghosh, A., Comerota, M., Rajpurohit, C. S., et al. (2026). Astrocytic sEH–EET signaling regulates microglial lysosomal function and suppresses the STING–Type I interferon pathway in Alzheimer’s disease. bioRxiv. https://doi.org/10.64898/2026.10.16.759679
Vancouver
Ghosh B, Wang S, Qi C, Ghosh A, Comerota M, Rajpurohit CS, et al. Astrocytic sEH–EET signaling regulates microglial lysosomal function and suppresses the STING–Type I interferon pathway in Alzheimer’s disease. bioRxiv. 2026. doi:10.64898/2026.10.16.759679.
BibTeX
@article{ghosh2026-549141c1,
author = {Ghosh, B. and Wang, S. and Qi, C. and Ghosh, A. and Comerota, M. and Rajpurohit, C. S. and Zeldin, D. C. and Zheng, H.},
title = {{Astrocytic sEH–EET signaling regulates microglial lysosomal function and suppresses the STING–Type I interferon pathway in Alzheimer’s disease}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.10.16.759679},
url = {https://doi.org/10.64898/2026.10.16.759679}
}
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