DAGLβ

DAGLβ (diacylglycerol lipase beta) is a serine hydrolase that catalyzes the hydrolysis of arachidonic acid-containing diacylglycerols to produce the endocannabinoid 2-arachidonoylglycerol (2-AG), thereby regulating lipid signaling networks associated with inflammatory responses^[1][2]. Mechanistically, DAGLβ modulates intracellular levels of 2-AG and arachidonic acid-derived lipid mediators involved in the activation of macrophages and microglia; consequently, it is considered a key regulator of endocannabinoid-dependent inflammatory signaling^[1][3]. In disease-relevant experimental models, pharmacological inhibition or genetic inactivation of DAGLβ remodels macrophage lipid metabolism, suppresses pro-inflammatory signaling pathways, and attenuates responses associated with inflammatory and neuropathic pain^[1][4]. Unlike DAGLα—which is primarily expressed in neurons and responsible for 2-AG synthesis in the central nervous system—DAGLβ exhibits higher activity in peripheral immune cells such as macrophages, microglia, and dendritic cells, suggesting distinct tissue-specific functions for the two isoforms^[3][5]. Recent lipidomics and chemoproteomics studies have further demonstrated that DAGLβ functions as a polyunsaturated fatty acid (PUFA)-specific triacylglycerol lipase in macrophages, thereby supporting immune cell-associated lipid metabolic processes^[2]. In experimental research, selective inhibitors such as KT109 effectively inhibit DAGLβ activity and are widely used to investigate inflammatory lipid signaling, endocannabinoid metabolism, and macrophage-mediated disease mechanisms^[1][4].