DAGLα

DAGLα (diacylglycerol lipase alpha) is a principal biosynthetic enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG) and is highly enriched in the central nervous system, where it regulates retrograde endocannabinoid signaling and neurotransmitter release through cannabinoid receptor activation.^[1][2][3] Mechanistically, DAGLα generates 2-AG from diacylglycerol downstream of phospholipase C signaling, providing the major source of activity-dependent 2-AG required for synaptic plasticity, axonal growth, and neuronal communication.^[1][2][4] Genetic deletion or manipulation of DAGLA markedly reduces brain 2-AG levels and disrupts endocannabinoid-mediated retrograde synaptic suppression, demonstrating its essential role in neuronal signaling networks.^[2][4][5] In disease-related contexts, dysregulated DAGLA/2-AG signaling has been associated with hepatocellular carcinoma progression through activation of YAP/TEAD-dependent transcriptional programs and enhanced tumor cell proliferation, invasion, and therapeutic resistance.^[6] Compared with the related isoform DAGLβ, which displays more restricted tissue- and cell-type-specific functions, DAGLα accounts for the majority of central nervous system 2-AG production and serves as the dominant neuronal 2-AG synthase in most brain regions.^[5][7][8] This functional distinction has made DAGLα an important target for mechanistic studies of endocannabinoid signaling and neurobiology.^[1][3] For experimental applications, pharmacological inhibitors such as DO34 reduce brain 2-AG levels and are widely used to investigate DAGL-dependent lipid signaling pathways and inflammatory phenotypes in vivo.^[9]