Edin_2025_J.Biol.Chem__110737

Epoxy fatty acids (EpFAs), including arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), are endogenously produced bioactive signaling molecules with diverse physiological effects, including vasodilation, anti-inflammation, and cardioprotection. EETs are generated by a subset of cytochromes P450 and their biological activity is reduced by hydrolysis to dihydroxyeicosatrienoic acids (DHETs) by epoxide hydrolases. Inhibition of soluble epoxide hydrolase (sEH) has shown significant therapeutic promise in preclinical models of disease. Despite the profound physiological impact of EETs and the therapeutic potential of sEH inhibitors, the precise signaling mechanisms by which EETs elicit their biological effects remain unknown. Many have sought to identity a high-affinity, EET-activated, G-protein-coupled receptor (GPCR). This review synthesizes current knowledge regarding the evidence supporting the existence of one or more EET-GPCRs and weighs this evidence against alternative or complementary EET signaling pathways. The breadth of these studies highlights the complexities and challenges in fully elucidating the precise molecular mechanisms of EET actions.