Verma_2026_J.Steroid.Biochem.Mol.Biol_261_107021

Soluble epoxide hydrolase (sEH) is a key enzyme in epoxy fatty acid (EpFA) metabolism, significantly affecting the balance of lipid mediators and the health of the central nervous system (CNS). This review explains the molecular biology, enzymatic activity, and clinical importance of sEH, emphasizing its role in converting anti-inflammatory epoxygenase metabolites into less active diols. Blocking sEH increases EpFA availability, leading to protective effects in experimental models of neuroinflammation, oxidative stress, and vascular failure linked to Alzheimer's, Parkinson's, and traumatic brain injury. The pharmacokinetics and chemistry of urea- and amide-based sEH inhibitors are also reviewed to highlight their development as potential CNS-targeted treatments. Recent preclinical and early clinical studies indicate that sEH inhibition may slow neurodegeneration and improve synaptic plasticity, thereby enhancing cognitive and behavioral functions. Overall, this review combines biochemical and pharmacological insights to support sEH as a promising target for treating neuroinflammation and neurodegenerative diseases characterized by disrupted lipid mediator signaling.