biostudies-literatureWang SNational Institute of Neurological Disorders and StrokeNIA NIH HHSCure Alzheimer's FundHarrington Discovery Institute, University HospitalsCure Alzheimer&apos;s FundNINDS NIH HHSNational Institute on Aging44https://www.ebi.ac.uk/biostudies/studies/S-EPMC12016400biostudies-literatureUnknown20(1)<h4>Background</h4>The epoxyeicosatrienoic acids (EETs) are derivatives of the arachidonic acid metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolysis by soluble epoxide hydrolase (sEH). Inhibition of sEH has been shown to stabilize the EETs and reduce neuroinflammation in Aβ mouse models of Alzheimer's disease (AD). However, the role of the sEH-EET signaling pathway in other CNS cell types and neurodegenerative conditions are less understood.<h4>Methods</h4>Here we investigated the mechanisms and functional role of the sEH-EET axis in tauopathy by treating PS19 mice with a small molecule sEH inhibitor TPPU and by crossing the PS19 mice with Ephx2 (gene encoding sEH) knockout mice. This was followed by single-nucleus RNA-sequencing (snRMolecular neurodegenerationInhibition of soluble epoxide hydrolase confers neuroprotection and restores microglial homeostasis in a tauopathy mouse model.PMC12016400A25-1690Not applicable066606068031093652020670Ghosh BLi HZheng HRajpurohit CWang BWang SGan LQi YHwang SHQi CXiong WHammock BDfalseInhibition of soluble epoxide hydrolase confers neuroprotection and restores microglial homeostasis in a tauopathy mouse model.<h4>Background</h4>The epoxyeicosatrienoic acids (EETs) are derivatives of the arachidonic acid metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolysis by soluble epoxide hydrolase (sEH). Inhibition of sEH has been shown to stabilize the EETs and reduce neuroinflammation in Aβ mouse models of Alzheimer's disease (AD). However, the role of the sEH-EET signaling pathway in other CNS cell types and neurodegenerative conditions are less understood.<h4>Methods</h4>Here we investigated the mechanisms and functional role of the sEH-EET axis in tauopathy by treating PS19 mice with a small molecule sEH inhibitor TPPU and by crossing the PS19 mice with Ephx2 (gene encoding sEH) knockout mice. This was followed by single-nucleus RNA-sequencing (snR2025-01-01T00:00:00Z2025 Apr2026-06-02T00:07:06.346Z2025-07-03T03:04:39.582ZS-EPMC120164004026418710.1186/s13024-025-00844-x