Nicotinamide adenine dinucleotide phosphate oxidase 4 in lung disease: a review of its biology and therapeutic potential

Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is a constitutively active enzyme that primarily produces hydrogen peroxide, a reactive oxygen species (ROS) with diverse cellular functions. While initially recognized for its role in oxidative stress, emerging evidence suggests that NOX4 plays a pivotal role in the pathogenesis of various lung diseases. This review delineates the structure characteristics of NOX4, emphasizing how its domain organization underlies a distinctive mode of molecular regulation. It further discusses current knowledge on the biological functions of NOX4-derived oxygen species, including their roles in modulating inflammation, cell death pathways, oxygen sensing, nuclear signaling, and metabolic reprogramming. Through these interconnected processes, NOX4 is positioned as a central mediator linking redox imbalance to cellular dysfunction. In addition, the contribution of NOX4 to the pathogenesis of major lung diseases, including idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), asthma, acute lung injury/acute respiratory distress syndrome (ALI/ARDS), and pulmonary hypertension are critically evaluated. Emerging therapeutic strategies targeting NOX4 are also discussed, together with key challenges associated with clinical translation, including isoform specificity, off-target effects, and tissue-selective delivery. Overall, this review provides an integrated framework for understanding NOX4 biology across multiple levels and highlights its potential as a therapeutic target in lung disease.