NADPH oxidase 1 and NADPH oxidase 2 (NOX1/NOX2)

The NOX1/NOX2 pathway refers to the enzymatic activity and signaling of NADPH oxidase 1 (NOX1) and NADPH oxidase 2 (NOX2), which are transmembrane proteins dedicated to the production of reactive oxygen species (ROS) [1, 11]. NOX2 is the prototypical member, primarily expressed in phagocytes where it generates the "respiratory burst" necessary for pathogen destruction, while NOX1 is found in the colon and vascular smooth muscle, regulating cell proliferation and signaling [4, 8, 22]. Dysregulation of these enzymes leads to excessive ROS production, driving oxidative stress and chronic inflammation associated with cardiovascular diseases, neurodegeneration, and fibrosis [2, 12, 16]. Therapeutic targeting of this pathway involves small-molecule inhibitors designed to reduce pathological ROS levels without compromising essential immune functions [1, 15]. Drugs such as the dual NOX1/NOX4 inhibitor setanaxib and the selective NOX2 inhibitor GSK2795039 are currently being explored for their potential to treat conditions like primary biliary cholangitis, diabetic nephropathy, and atherosclerosis [5, 10, 13, 24]. This pathway represents a significant focus in drug development due to its central role in redox-mediated tissue damage across multiple organ systems [16, 20]. Challenges in targeting these enzymes include achieving isoform selectivity to avoid off-target effects and maintaining the physiological ROS signaling required for normal cellular processes [11, 16]. Clinical trials are ongoing to evaluate the efficacy and safety of these inhibitors in various rare and chronic diseases [14, 19].

Other names

NOX1NOX2NADPH oxidase 1NADPH oxidase 2gp91phoxCYBBMOX1Cytochrome b-245 heavy chain

Inhibition of NADPH oxidase enzymatic activity to reduce the generation of reactive oxygen species (ROS) such as superoxide and hydrogen peroxide.