Yao_2026_Eur.J.Med.Chem_308_118684

Soluble epoxide hydrolase (sEH) is the key enzyme involved in endogenous epoxyeicosatrienoic acids (EETs) metabolism. sEH inhibition leads to the accumulation of EETs, which exhibit a variety of beneficial physiological effects, such as anti-inflammatory, analgesic, cardiovascular protective, and metabolic regulatory effects. EETs have become an important therapeutic target for inflammation, pain, metabolic diseases, and neurodegenerative diseases. In this article, we summarize the biological functions and protein characteristics of sEH. Based on this, we systematically summarize advances in the field of inhibitors. The search for highly active and selective inhibitors remains centered on the optimization of urea and amide scaffolds; meanwhile, research on sEH-based multi-target inhibitors (e.g., sEH/COX-2, sEH/PPARgamma) is advancing rapidly, aiming to enhance efficacy and reduce side effects through synergistic mechanisms. Structurally diverse sEH inhibitors have been found in natural products. Finally, we critically highlight pivotal knowledge gaps-specifically the under-explored regulatory potential of the N-terminal phosphatase domain (sEH-P) and the bottleneck of blood-brain barrier (BBB) permeability-and propose a translational roadmap to accelerate the progression from mechanistic insights to clinical precision medicine.