N-acylethanolamines (NAEs), including N-palmitoylethanolamine (PEA), N-oleoylethanolamine (OEA), N-arachidonoylethanolamine (AEA, anandamide), N-docosahexaenoylethanolamine (DHEA, synaptamide) and their oxygenated metabolites are a lipid messenger family with numerous functions in health and disease, including inflammation, anxiety and energy metabolism. The NAEs exert their signaling role through activation of various G protein-coupled receptors (cannabinoid CB₁ and CB₂ receptors, GPR55, GPR110, GPR119), ion channels (TRPV1) and nuclear receptors (PPAR-α and PPAR-γ) in the brain and periphery. The biological role of the oxygenated NAEs, such as prostamides, hydroxylated anandamide and DHEA derivatives, are less studied. Evidence is accumulating that NAEs and their oxidative metabolites may be aberrantly regulated or are associated with disease severity in obesity, metabolic syndrome, cancer, neuroinflammation and liver cirrhosis. Here, we comprehensively review NAE biosynthesis and degradation, their metabolism by lipoxygenases, cyclooxygenases and cytochrome P450s and the biological functions of these signaling lipids. We discuss the latest findings and therapeutic potential of modulating endogenous NAE levels by inhibition of their degradation, which is currently under clinical evaluation for neuropsychiatric disorders. We also highlight NAE biosynthesis inhibition as an emerging topic with therapeutic opportunities in endocannabinoid and NAE signaling.

N-酰基乙醇胺(NAEs)，包括N-棕榈酰乙醇胺(PEA)、N-油酰乙醇胺(OEA)、N-花生四烯酰乙醇胺(AEA, anandamide)、N-二十二碳六烯酰乙醇胺(DHEA, synaptamide)及其含氧代谢物是一个脂质信使家族，具有许多在健康和疾病中发挥作用，包括炎症、焦虑和能量代谢。NAEs 通过激活各种 G 蛋白偶联受体（大麻素 CB ₁和 CB ₂受体，GPR55，GPR110，GPR119），离子通道（TRPV1）和大脑和周围的核受体（PPAR-α和PPAR-γ）。含氧 NAE（例如前列腺酰胺、羟基化 anandamide 和 DHEA 衍生物）的生物学作用研究较少。越来越多的证据表明，NAE 及其氧化代谢物可能受到异常调节，或者与肥胖、代谢综合征、癌症、神经炎症和肝硬化等疾病的严重程度有关。在这里，我们全面回顾了 NAE 的生物合成和降解、脂肪氧化酶、环氧合酶和细胞色素 P450 对它们的代谢以及这些信号脂质的生物学功能。我们讨论了通过抑制其降解来调节内源性 NAE 水平的最新发现和治疗潜力，目前正在对神经精神疾病进行临床评估。我们还强调 NAE 生物合成抑制是一个新兴主题，在内源性大麻素和 NAE 信号传导方面具有治疗机会。