NAPEPLD encodes N-acyl phosphatidylethanolamine phospholipase D, a zinc metallohydrolase that catalyzes the hydrolysis of N-acyl-phosphatidylethanolamines (NAPEs) to generate N-acylethanolamines (NAEs), including the endocannabinoid anandamide, and phosphatidic acid 1. The enzyme plays a central role in endocannabinoid system homeostasis, with bile acids serving as allosteric activators that enhance substrate specificity 2. NAPEPLD mutations cause canine leukoencephalomyelopathy, a white matter disorder implicating the enzyme in myelin homeostasis and suggesting it as a candidate gene for human myelination disorders 3. Beyond neurological function, NAPEPLD regulates energy homeostasis and body temperature by promoting brown/beige adipocyte differentiation 4. Clinically, NAPEPLD is a previously unknown target of thiazide diuretics, explaining their antihypertensive and diuretic mechanisms 5. NAPE-PLD activation enhances macrophage efferocytosis, suggesting therapeutic potential for cardiometabolic diseases where NAPEPLD expression is reduced in atherosclerotic lesions 6. Spermatozoa express circular NAPEPLD transcripts that interact with oocyte microRNAs, potentially regulating early embryonic development 7.