Resolving the Dual Nature of NADPH Oxidase 4 in Cardiac Fibrosis for Selective Therapeutic Targeting: A Narrative Review

Cardiac fibrosis is a common route leading to heart failure and arrhythmia. However, there are no cardio-selective antifibrotic drugs currently approved. NADPH oxidase 4 (NOX4), which predominantly produces hydrogen peroxide and requires no cytosolic activator subunits, is regulated by expression, protein stability and post-translational modification. Its intracellular organelle localization makes it a potential redox-medicine target. Setanaxib, the first dual NOX1/NOX4 inhibitor under clinical development, is not NOX4-selective and remains unapproved. This narrative review of MEDLINE literature presents genetic, mechanistic, pharmacological and clinical evidence of associations between NOX4 and cardiac fibrosis in cardiomyocytes, fibroblasts, endothelial and immune cells, including effects of cardiovascular drugs. NOX4 can have pro-fibrotic effects through TGF-β1/Smad activation, regulated cardiomyocyte death, inflammatory signals and atrial/ventricular ion-channel remodelling. Yet, genetic studies report divergent findings reflective of context-dependent influences. NOX4 in the endoplasmic reticulum and mitochondria-associated membranes may promote autophagy and survival, whereas persistent high NOX4-derived ROS in stressed myocardium results in mitochondrial injury and fibrosis. Endothelial NOX4 seems mainly protective. Dual NOX1/NOX4 inhibition and preferential NOX4-targeting have been shown to have antifibrotic effects in pre-clinical cardiac models, although there is no clinical evidence. Divergences may be explained on four axes: ROS level, subcellular compartment, cell type and disease-state. A reasonable approach to translating NOX4-targeted pharmacology into cardiac antifibrotic therapy would be to adopt strategies that are specific to compartment and cell type.