European journal of pharmacologyOct 23, 2026

Understanding the Two Roles of NADPH Oxidase 4 in Heart Scarring to Guide Targeted Treatments

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 24, 2026

Abstract

Cardiac fibrosis is associated with heart failure and arrhythmia, and current treatments lack approved cardio-selective antifibrotic drugs.

NADPH oxidase 4 (NOX4) may contribute to cardiac fibrosis through various cellular mechanisms.
NOX4 is involved in pro-fibrotic signaling pathways, including TGF-β1/Smad activation and inflammatory responses.
Different genetic studies show varying roles of NOX4, indicating context-dependent influences on cardiac health.
While NOX4 may promote autophagy and cell survival in some contexts, excessive NOX4 activity can lead to mitochondrial damage and fibrosis.
Pre-clinical models suggest that dual inhibition of NOX1/NOX4 may have antifibrotic effects, but this has not yet been demonstrated in clinical settings.
Variations in NOX4’s role may depend on factors such as reactive oxygen species levels, cell type, and the specific disease state.

Simplified

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 localisation 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.

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Understanding the Two Roles of NADPH Oxidase 4 in Heart Scarring to Guide Targeted Treatments

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