Beyond conventional therapy: NOX4 as a promising target in cardiomyopathy

Cardiomyopathy refers to disorders marked by structural and functional irregularities in the heart muscle, occurring independently of other conditions that might explain these abnormalities. The most common types are dilated and hypertrophic cardiomyopathies, while Takotsubo, restrictive, left ventricular non-compaction, and arrhythmogenic right ventricular cardiomyopathies are rarer. These conditions cause ventricular hypertrophy, fibrosis, myocardial dysfunction, and chamber dilation due to responses to stressors such as pressure overload, myocardial infarction, inflammation, diabetes, and cardiotoxic drugs. Oxidative stress, marked by an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, plays a key role in the cardiac pathophysiology of various cardiomyopathy subtypes. In the heart, ROS are mainly generated by NADPH oxidase (NOX) under normal and pathological conditions. NADPH oxidase 4 (NOX4) is a major source of ROS within cardiomyocyte mitochondria. Research shows that ROS produced by NOX4 contribute to pathological cardiac remodeling, myocardial inflammation, fibrosis, apoptosis, genetic mutations, and hypertrophy. NOX4 inhibition or deletion alleviates these harmful effects. This review explores NOX4-driven ROS production across cardiomyopathy subtypes and its implications. Understanding the roles of NOX4 in cardiac health will help develop innovative therapeutic strategies for preventing and managing cardiomyopathy. This review aims to provide a synthesis of current knowledge regarding NOX4's function and regulatory mechanisms in cardiomyopathy.