Altered biopterin-related cofactor metabolism in the aqueous humor of glaucoma patients

Glaucoma is a leading cause of irreversible blindness worldwide and is primarily managed through IOP reduction, though its underlying pathophysiology remains incompletely understood. This study investigates metabolic alterations in glaucoma via targeted metabolomic profiling to identify potential biomarkers and pathogenic mechanisms. Aqueous humor samples were collected from 191 patients at Pauls Stradins Clinical University Hospital immediately before the initiation of cataract surgery, ensuring preoperative conditions. Quantitative metabolite profiling was conducted using liquid chromatography coupled to a Thermo Orbitrap Exploris 120 mass spectrometer. A significant association was observed between open-angle glaucoma and the presence of PEXS (χ²(1) = 9.96, p = 0.002, Cramer's V = 0.228). Several metabolites, including tryptophan, leucine, phenylalanine, and glutamine, were significantly upregulated in glaucoma patients (all p < 0.003, FDR = 0.0358), with tyrosine showing a similar trend (p = 0.0034, FDR = 0.0358). These findings suggest dysregulation of aromatic amino acid metabolism and potential impairment of amino acid hydroxylases, possibly linked to reduced tetrahydrobiopterin (BH4) availability. Disruption in BH4 regeneration-driven by oxidative stress or MTHFR polymorphisms-may impair nitric oxide synthesis and contribute to disease progression. Elevated glutamine and leucine levels could reflect compensatory neuroprotective mechanisms against excitotoxic damage. Our findings suggest that altered biopterin-related cofactor metabolism in aqueous humor may disrupt nitric oxide production and exacerbate oxidative stress, both of which are key factors in glaucoma pathogenesis. These insights highlight the potential of oxidative stress-related biomarkers and antioxidant-based strategies for future glaucoma diagnosis and therapy.