This review details how soluble epoxide hydrolase (sEH) degrades anti-inflammatory epoxy fatty acids, summarizes urea- and amide-based sEH inhibitor chemistry and PK, and presents preclinical and early clinical evidence that sEH inhibition can reduce neuroinflammation and provide neuroprotection…

It identifies sEH as a druggable target with mechanistic linkage to neuroinflammation and lipid signaling and points to actionable small-molecule inhibitors and translational data that could be leveraged for Parkinson's therapeutic development.

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.