The Oxidative Paradigm in Glaucoma: Pathogenic Mechanisms Beyond Intraocular Pressure

Abstract

Background: Glaucoma is a chronic optic neuropathy traditionally managed by lowering intraocular pressure (IOP), yet progression may occur despite controlled or normal IOP, suggesting additional pathogenic pathways. Objective: To synthesize contemporary evidence describing oxidative stress–mediated mechanisms that contribute to glaucomatous damage beyond IOP alone and to summarize emerging therapeutic implications. Methods: This narrative review synthesized evidence identified through PubMed and Google Scholar searches (2021–2025), prioritizing 15 core publications for mechanistic integration and using foundational sources for background context. Results: Reactive oxygen species accumulation and impaired antioxidant defenses are consistently linked with trabecular meshwork dysfunction, extracellular matrix remodeling, and reduced aqueous outflow, which may increase IOP instability. In parallel, mitochondrial dysfunction, impaired bioenergetics, and glial-mediated neuroinflammation contribute to retinal ganglion cell vulnerability and optic nerve head degeneration, providing a plausible framework for progression in normal-tension and treatment-resistant phenotypes. Biomarker studies commonly report increased oxidative injury markers with reduced antioxidant capacity, but clinical heterogeneity limits causal inference. Conclusion: Oxidative stress and mitochondrial dysfunction plausibly contribute to glaucoma pathophysiology through pressure-dependent and pressure-independent mechanisms. Adjunctive neuroprotective strategies targeting redox balance and mitochondrial resilience are promising but require standardized biomarkers and adequately powered clinical trials.