One-carbon metabolism and retinal ganglion cell vulnerability in glaucoma: metabolic pathway dysregulation, ocular evidence, and translational neuroprotection.

PURPOSE: To synthesize evidence linking one-carbon metabolism to retinal ganglion cell (RGC) vulnerability and pressure-independent neurodegeneration in glaucoma, while distinguishing direct glaucoma-relevant evidence, indirect biological support, and mechanistic hypotheses. METHODS: We conducted a critical narrative review of human ocular and systemic metabolomics, conventional biomarkers, nutritional epidemiology, experimental retinal injury and glaucoma models, and early translational studies. The metabolomics evidence base comprised 26 reports (17 ocular and 9 systemic), evaluated by glaucoma subtype, specimen, analytical platform, analyte direction, effect-size availability, and cohort independence. RESULTS: Under the operational cross-study criteria used in this review, five aqueous-humor analytes recurred across independent primary open-angle glaucoma (POAG) cohort families, all with compatible increases: threonine, lysine, histidine, arginine, and creatinine. Broader cross-study convergence was strongest at the amino-acid, membrane-lipid, energy/purine/tricarboxylic acid (TCA), and redox pathway levels. Exfoliation-related ocular studies showed no exact recurrent analyte, whereas systemic evidence was most consistent for diglyceride/triglyceride class-level associations. Direct evidence includes human glaucoma cohorts and protection with combined vitamins B6, B9, and B12 plus choline in experimental glaucoma. Non-glaucoma retinal, RGC, and glial models provide indirect support, whereas compartment-specific ocular flux, a transsulfuration-to-axon causal chain, and axis-specific choline/betaine effects remain hypotheses. Human interventional evidence is limited to an early-phase protocol. CONCLUSION: One-carbon metabolism is a candidate biological framework for mechanistic and target-engagement studies, not a validated biomarker panel or established supplementation strategy. Clinical efficacy of one-carbon pathway modulation or related supplementation in glaucoma has not been established.