NADPH oxidase 1 and NADPH oxidase 4 (NOX1/NOX4)

NADPH oxidase 1 (NOX1) and NADPH oxidase 4 (NOX4) are transmembrane enzymes that catalyze the transfer of electrons from NADPH to molecular oxygen, generating reactive oxygen species (ROS) such as superoxide and hydrogen peroxide [1, 4]. NOX1 primarily produces superoxide in response to various agonists and is involved in acute signaling, while NOX4 is constitutively active and generates hydrogen peroxide, serving as a critical mediator in redox signaling and cellular homeostasis [9, 16]. Pathological overactivation of these isoforms is a key driver in the development of fibrosis and chronic inflammation across multiple organs, including the liver, kidneys, and lungs [1, 8]. Specifically, NOX1 and NOX4 facilitate pro-fibrotic signaling through pathways such as TGF-beta and PDGF, leading to excessive extracellular matrix deposition and tissue scarring [4, 13]. Therapeutic targeting of this dual complex, notably by the small molecule setanaxib (GKT137831), has shown promise in clinical trials for conditions like primary biliary cholangitis and diabetic kidney disease by reducing oxidative stress without compromising the immune functions associated with the NOX2 isoform [1, 10, 15]. Unlike NOX2, which is essential for phagocytic host defense, NOX1 and NOX4 are considered safer therapeutic targets with fewer spontaneous pathologies observed in genetic knockout models [4, 15]. However, biotech analysts should note that some studies suggest basal NOX4 activity may have protective roles in vascular and renal health, necessitating careful monitoring of long-term inhibition to avoid disrupting beneficial physiological redox signaling [4, 6, 9].

Other names

NADPH oxidase 1NADPH oxidase 4NOX1NOX4GKT137831 target

Direct inhibition of the catalytic activity of NOX1 and NOX4 enzymes, leading to reduced production of reactive oxygen species (ROS) and attenuation of pro-fibrotic and pro-inflammatory signaling pathways [1, 3, 5].