NAXE (NAD(P)HX epimerase) catalyzes the epimerization of damaged NAD(P)H forms (NAD(P)HX) generated through enzymatic or heat-dependent hydration, enabling subsequent repair by NAD(P)HX-hydrate dehydratase 1. This function is essential for maintaining cellular redox homeostasis, as NAXE deficiency leads to accumulation of toxic NAD(P)HX metabolites and depletion of functional NAD(P)H 2. Beyond metabolite repair, NAXE promotes cholesterol efflux from endothelial cells to HDL, regulating angiogenesis [UniProt reference]. Pathogenic NAXE mutations cause progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL1), a severe early-onset neurometabolic disorder characterized by rapidly progressive neurological deterioration, seizures, and often fatal decompensation following infection or fever 34. Disease mechanisms involve acute NAD+ depletion, mitochondrial dysfunction, and impaired antioxidant defense, with altered lipidomics evident during crisis 2. In hepatocellular carcinoma, NAXE downregulation promotes tumor progression through ROS accumulation and HIF-1α activation, identifying NAXE as a tumor suppressor 5. Niacin supplementation shows promise in ameliorating metabolomic abnormalities and clinical symptoms in NAXE deficiency patients 2.