NADPH oxidase 2 and NADPH oxidase 4 (NOX2/4)

NADPH oxidase 2 (NOX2) and NADPH oxidase 4 (NOX4) are critical transmembrane enzymes dedicated to the production of reactive oxygen species (ROS). NOX2, primarily expressed in phagocytes, is essential for the innate immune system's respiratory burst, which facilitates the destruction of invading pathogens [1, 3]. In contrast, NOX4 is constitutively active and widely expressed in the kidneys, blood vessels, and fibroblasts, where it produces hydrogen peroxide to act as a secondary messenger in oxygen sensing and cellular signaling [2, 4]. Pathological overactivation of these isoforms is a major driver of oxidative stress, contributing to the progression of chronic inflammatory and fibrotic diseases, including diabetic nephropathy and idiopathic pulmonary fibrosis [3, 5]. Therapeutic targeting of NOX2 and NOX4 aims to suppress excessive ROS production to prevent tissue damage and fibrotic remodeling. Clinical candidates like Setanaxib (a NOX1/4 inhibitor) and various preclinical dual inhibitors are being explored to treat these conditions by modulating the redox environment without completely abolishing essential physiological ROS functions [3, 6].

Other names

Cytochrome b-245 heavy chain (NOX2)gp91phox (NOX2)CYBB (NOX2)RENOX (NOX4)Kidney oxidase-1 (NOX4)KOX-1 (NOX4)

Inhibition of the catalytic activity of NOX2 and NOX4 enzymes to prevent the transfer of electrons from NADPH to molecular oxygen, thereby reducing the generation of superoxide (O2-) and hydrogen peroxide (H2O2) and mitigating downstream oxidative stress and pro-fibrotic signaling pathways [3, 4].