NOX4 (NADPH oxidase 4) is a constitutively active enzyme that generates hydrogen peroxide (H2O2) rather than superoxide as its primary reactive oxygen species product 1. Unlike other NOX family members, NOX4 functions as a key oxygen sensor through its unique structural properties that enable continuous H2O2 production 1. The enzyme plays critical roles in cellular processes including proliferation, migration, and cell death through oxidative signaling 1. NOX4 exhibits tissue-specific functions with both protective and pathogenic roles depending on cellular context. In hepatocytes, NOX4 provides cytoprotective antioxidant defense by activating NFE2L2 (Nrf2) signaling, preventing progression from fatty liver to steatohepatitis and fibrosis 2. However, NOX4 also promotes pathological processes including cancer progression through enhancement of angiogenesis, metastasis, and drug resistance mechanisms 13. In cancer-associated fibroblasts, NOX4 maintains immunosuppressive phenotypes that exclude CD8+ T cells from tumors 4. The enzyme contributes to neurodegeneration by promoting ferroptosis in astrocytes through oxidative stress-induced lipid peroxidation and mitochondrial dysfunction 5. NOX4 also participates in cardiac hypertrophy and renal fibrosis pathogenesis 67. Given its diverse pathological roles, NOX4 represents a promising therapeutic target, with inhibitors showing efficacy in preclinical models of cancer, fibrosis, and cardiovascular disease.