Targeting NOX inhibitors in neurodegeneration: a therapeutic perspective

Neurodegenerative diseases are characterized by progressive neuronal loss, cognitive decline, and motor dysfunction driven by oxidative stress and neuroinflammation. NADPH oxidases (NOX) are a major source of reactive oxygen species (ROS) in the central nervous system, contributing to oxidative damage, mitochondrial dysfunction, and neuroinflammatory responses. Overactivation of NOX enzymes, particularly NOX-1, NOX-2, and NOX-4, has been implicated in neuronal injury and disease progression. NOX inhibitors have shown promise in pre-clinical models by reducing ROS production, modulating neuroinflammatory pathways, and preserving neuronal integrity. Despite these encouraging findings, clinical research remains in early stages, with ongoing studies focused on evaluating NOX inhibitors in neurodegeneration. NOX inhibition represents a promising therapeutic strategy for neurodegeneration. However, challenges such as achieving isoform selectivity, improving drug bioavailability, and overcoming blood-brain barrier penetration must be addressed for successful clinical translation. This review provides a therapeutic perspective on NOX inhibition in neurodegenerative diseases, discussing the current state of pre-clinical and clinical research, highlighting key challenges, and proposing directions for future research aimed at optimizing NOX-targeted therapies for clinical application.