Epoxide Hydrolase Family: Biological Functions, Disease Mechanisms, and Emerging Therapeutic Strategies

Epoxide hydrolases (EHs) constitute a conserved enzyme family that catalyzes the hydrolysis of epoxides into less reactive diols. Beyond their canonical roles in xenobiotic detoxification, EHs have emerged as critical regulators of lipid metabolism, redox balance, and inflammatory signaling. Accumulating evidence implicates EH family members, particularly Ephx1 (microsomal EH) and Ephx2 (soluble EH), in cardiovascular diseases, cancer, neurodegeneration, metabolic disorders, and other pathological conditions. More recently, studies have uncovered specialized functions of Ephx3 and Ephx4, broadening our understanding of EH biology and highlighting their tissue-specific roles in skin homeostasis and lipid signaling. Here, we systematically review the structural features, catalytic mechanisms, and physiological functions of EHs, with an emphasis on their regulatory networks in human diseases. We further discuss advances in genetic, epigenetic, and translational studies that connect EHs to disease susceptibility and progression. Finally, we evaluate the therapeutic potential and challenges of targeting EHs, particularly soluble EH inhibitors, and propose future research directions to bridge basic discoveries with clinical translation. This review aims to provide a comprehensive framework for understanding the multifaceted roles of EHs and to inspire novel strategies for precision medicine.