ENOX2 (ecto-NOX disulfide-thiol exchanger 2) is a tumor-associated NADH oxidase predominantly expressed on cancer cell surfaces that plays critical roles in cancer cell growth and survival 1. The protein functions as a terminal oxidase in plasma membrane electron transport, converting cytosolic NADH and modulating cellular redox balance 2. ENOX2 demonstrates cancer-specific expression patterns, being upregulated across multiple cancer types including chrX myeloid leukemia through BCR-ABL1-dependent mechanisms 3, oral cancers where it regulates stemness properties through interactions with SOX2 4, nasopharyngeal carcinoma 5, and melanoma 6. Mechanistically, ENOX2 inhibition leads to cytosolic NADH accumulation, which modulates sphingolipid metabolism by inhibiting sphingosine kinase 1 and stimulating neutral sphingomyelinase, ultimately shifting the ceramide/sphingosine-1-phosphate balance toward apoptosis 2. Clinically, ENOX2 serves as both a prognostic biomarker and therapeutic target, with high expression correlating with poor survival outcomes 6 and enhanced detection possible through aptamer-based biosensors 7. Inhibitors like phenoxodiol demonstrate chemosensitizing effects, enhancing responses to conventional therapies 85.