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Editors Selection IGR 15-1

Basic Science: B vitamins and choline as neuroprotective agents: the metabolic angle

Comment by Katharina Bell & Jonathan Crowston on:

127088 Dysfunctional one-carbon metabolism identifies vitamins B, B, B, and choline as neuroprotective in glaucoma, Tribble JR; Wong VHY; Stuart KV et al., Cell reports. Medicine, 2025; 6: 102127

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Tribble and colleagues provide an in-depth investigation into the role of homocysteine in glaucoma pathogenesis that advances our understanding of metabolic vulnerability in glaucoma. This study repositions elevated homocysteine from a putative causal factor to a biomarker of disrupted one-carbon metabolism within the retina and optic nerve head. Through convergent evidence from rodent models, single cell RNAseq and human genetic and clinical datasets. The authors demonstrated that dysregulation of the methionine, folate, and transsulfuration pathways occurs early in disease and precedes overt retinal ganglion cell (RGC) loss. The identification of deficits in vitamin-dependent metabolic machinery—particularly B6, B9, B12, and choline—provides a mechanistic framework linking impaired methylation capacity, redox homeostasis, and mitochondrial resilience to glaucomatous neurodegeneration. Importantly, supplementation with these cofactors conferred robust structural and functional neuroprotection in both acute and chronic ocular hypertension models underpinning good potential for translation to glaucoma patients. This work is particularly impactful in that it integrates negative human data—Mendelian randomization, longitudinal visual field analysis, and population dietary studies—to constrain interpretation and avoid over-attribution of causality to homocysteine itself. Despite the large amount of data in this study, several questions remain unresolved. The precise cellular mechanisms by which vitamin supplementation restores RGC resilience was not directly tested, and it remains unclear whether protection is mediated through normalization of one-carbon flux, improved mitochondrial function, epigenetic regulation, or indirect effects on glial or immune populations. Additionally, the supraphysiological dosing required for efficacy in animal models, particularly for folate and choline, may limit direct translation into humans and optimal dosing strategies will need to be defined. This study further contributes important new evidence that metabolic insufficiency is an early and actionable feature of glaucoma and provides a compelling rationale for targeting one-carbon metabolism in future mechanistic and clinical studies.

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