Overcoming Oxidative Stress in Parkinson’s Disease: NADPH Oxidase 4 (NOX4) as a Potential Therapeutic Target

Parkinson’s disease (PD) lacks effective disease-modifying therapies (DMTs). While oxidative stress drives PD pathogenesis, broad-spectrum antioxidants frequently fail in clinical trials due to limited specificity and poor cerebral bioavailability. In PD, reactive oxygen species (ROS) arise from multiple intracellular sources, among which mitochondrial dysfunction is widely recognized as a fundamental driver, while nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4), a constitutively active NOX isoform that predominantly generates hydrogen peroxide (H2O2), has emerged as an important enzymatic contributor in the central nervous system. This review systematically examines the important role of NOX4 in PD and proposes a mechanistic framework by which NOX4-derived ROS contribute to PD progression. NOX4-derived ROS may directly promote mitochondrial dysfunction, proteostasis disruption, neuroinflammation, and ferroptosis. More importantly, NOX4-derived ROS may aggravate mitochondrial dysfunction to increase mitochondrial ROS production, thereby promoting PD progression indirectly. We systematically summarize the emerging NOX4-targeted strategies, including highly selective small-molecule inhibitors, natural products, gene therapies, and blood–brain barrier-penetrating nanodrug delivery systems. NOX4 should be viewed as an important regulator and potential amplifier that can affect multiple pathogenic processes in PD, thereby representing a promising avenue for the development of DMTs for PD.