Zhao_2025_Adv.Pharmacol_102_237

Soluble epoxide hydrolase (sEH), encoded by the EPHX2 gene, is a critical enzyme involved in the metabolism of polyunsaturated fatty acids, specifically anti-inflammatory epoxy fatty acids (EpFAs). By converting EpFAs into less active forms, sEH promotes inflammation. Preclinical data using knock-out and overexpression of the Ephx2 gene have demonstrated its key role in the development and progression of symptoms in various disease models. Inhibition of sEH increases EpFAs, thereby enhancing their anti-inflammatory effects and reducing the levels of pro-inflammatory mediators. Numerous preclinical studies suggest that sEH inhibitors show promise in reducing inflammation and its related symptoms across various diseases, highlighting their therapeutic potential. This chapter reviews the role of sEH in the development and progression of various disorders including psychiatric disorders (depression, schizophrenia, autism spectrum disorder), neurological disorders (Alzheimer's disease, Parkinson's disease, brain injury), and pain.