Li_2025_Eur.J.Med.Chem_302_118349

Soluble epoxide hydrolase (sEH) plays a central role in regulating the metabolism of epoxyeicosatrienoic acids (EETs) and governs multiple pathophysiological cascades, establishing it as a key therapeutic target for metabolic, cardiovascular, cerebrovascular, inflammatory and pain-related disorders. Although several potent sEH inhibitors have advanced to clinical evaluation, classical single-target agents exhibit limited efficacy and a propensity for resistance when confronted with the multifactorial pathogenic nature of complex diseases. In recent years, the emerging paradigm of multi-target drug discovery offers a route to surmount these limitations. By synergistically modulating interacting pathways, dual-target inhibitors can not only reinforce therapeutic efficacy and reduce risk of drug resistance, but also minimize off-target effects caused by excessive intervention of a single target. Accordingly, a growing body of evidence indicates that dual-target sEH inhibitors demonstrate superior in vivo efficacy and safety compared to single-target sEH inhibitors. This review systematically summarizes the current research progress in dual-target sEH inhibitors, and give a comprehensive analysis of the rational design, structure-activity relationship (SAR) optimization and translational prospects of dual-target sEH ligands. It is expected to provide a theoretical foundation and innovative directions for developing efficient and safe multi-target sEH therapeutic strategies.