(±)17(18)-EpETE is an active metabolite of the ω-3 fatty acid eicosapentaenoic acid (EPA) formed via epoxidation of the 17,18 double bond by the cytochrome P450 (CYP) isoform CYP1A2 and an agonist of sphingosine-1-phosphate receptor 1 (S1P1).^1,2 It binds to S1P1 (Ki = 0.57 nM) and activates S1P1 in a bioluminescence resonance energy transfer (BRET) assay using HEK293T cells expressing human S1P1 (EC50 = 8.93).¹ (±)17(18)-EpETE (100 nM) also increases outward potassium efflux in rat vascular smooth muscle cells expressing large-conductance calcium-activated potassium channels (KCa1.1/BK).³ It inhibits oscillatory shear stress- or TNF-α-induced increases in vascular cell adhesion molecule-1 (VCAM1) levels in human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner.¹ (±)17(18)-EpETE (1 µM) increases levels of phosphorylated endothelial nitric oxide synthase (eNOS), as well as prevents TNF-α-induced increases in levels of IκBα and phosphorylated levels of IKKα and p65 in HUVECs. In vivo, (±)17(18)-EpETE decreases tissue levels of VCAM1 and intracellular adhesion molecule-1 (ICAM1) and reduces the number of atherosclerotic lesions in the carotid arteries of wild-type but not S1pr1-/- mice in a model of atherosclerosis induced by arterial ligation and the Pcsk9 mutant Pcsk9N377Y.