The Metabolic Architecture of Glaucoma: A Unified Framework of Cofactor Failure and Kynurenine Dysregulation

Glaucoma remains a primary cause of blindness, yet its pathogenesis often extends beyond intraocular pressure (IOP). This review integrates four converging lines of metabolic evidence-aqueous humor (AH) metabolomics, kynurenine pathway (KP) activity, tetrahydrobiopterin (H4BIP) biology, and NAD/one-carbon dysfunction-into a testable framework for retinal ganglion cell vulnerability. By utilizing a systematic AH metabolomics atlas covering glaucoma, pseudoexfoliation, and diabetes on a standardized HILIC-LC-HRMS platform, we demonstrate that, while aromatic amino acid elevations are non-specific markers, kynurenine monooxygenase (KMO) upregulation is a condition-specific glaucoma signature. These local findings are corroborated by systemic evidence: POAG patients exhibit significant folic acid deficiency (p = 0.007) and elevated alpha-1-antitrypsin (AAT). Critically, AAT correlates inversely with both serum folate (r_s = -0.485, p < 0.001) and retinal nerve fiber layer thickness (r_s = -0.386, p = 0.017), providing the first in-patient evidence linking systemic inflammation to structural optic nerve damage. We conclude that KMO serves as a critical enzymatic node linking tryptophan metabolism, H4BIP availability, and NAD synthesis. These results characterize glaucoma as a disease of progressive cofactor failure and define a research agenda for multimodal metabolic neuroprotection.