NOXO1 (NADPH oxidase organizer 1) is a cytoplasmic scaffold protein that constitutively potentiates superoxide generation by NOX1 and NOX3 complexes 1. Beyond its canonical ROS-generating function, NOXO1 exhibits multiple NOX1-independent roles: it regulates EGFR signaling through interaction with Erbin, delaying EGF-induced kinase activation 2, and promotes endosomal/lysosomal biogenesis via TFEB activation in an Erbin-dependent manner 3. Subcellular localization to the cytoskeleton, regulated by D-box mutations, modulates NOX1 activity 4. CYLD-mediated ubiquitination destabilizes NOXO1 protein, suppressing excessive ROS generation and tumor progression 5. In pathophysiology, NOXO1 deletion prevents diabetes-induced vascular dysfunction without compensating for p47phox loss, indicating distinct regulatory roles 6. NOXO1 upregulation drives smoke-induced emphysema and pulmonary hypertension through peroxynitrite formation 7, making it a potential COPD therapeutic target. Additionally, NOXO1 DNA methylation participates in uterine fibroid pathogenesis via immune cell infiltration regulation 8. These findings establish NOXO1 as a multifunctional adaptor protein with both ROS-dependent and ROS-independent roles in vascular, pulmonary, and reproductive pathology.