ETNPPL (ethanolamine-phosphate phospho-lyase) is a pyridoxal-phosphate-dependent metabolic enzyme localized to the mitochondrial matrix that catalyzes the breakdown of phosphoethanolamine into ammonia, inorganic phosphate, and acetaldehyde 1. The enzyme plays critical roles in lipid homeostasis across multiple tissues. In the brain, ETNPPL is astrocyte-specific and fasting-induced, regulating phospholipid composition during development and in response to glucocorticoids; loss of ETNPPL alters the phospholipid profile, increasing total phosphatidylethanolamine and polyunsaturated fatty acids 2. In hepatocytes, ETNPPL reduces cellular phosphoethanolamine synthesis, decreasing PE availability and increasing the PC:PE ratio associated with metabolic dysfunction-associated steatotic liver disease 3. ETNPPL mediates hyperinsulinemia-induced insulin resistance through SIK1/ROS-dependent inactivation of PI3K/AKT signaling 1, and palmitic acid-induced insulin resistance through ARG2/ROS-mediated autophagy impairment 4. Clinically, ETNPPL is downregulated in hepatocellular carcinoma with diagnostic value (AUC=0.9089) and prognostic significance; overexpression inhibits HCC cell migration and invasion 5. In gliomas, ETNPPL downregulation promotes malignant progression, with ETNPPL expression inversely correlated to glioma grade 6. ETNPPL expression is reduced in Parkinson's disease dopaminergic neurons, correlating with disease pathology 7, and identified as a potential biomarker for sarcopenia diagnosis 8.