Metabolic Mapping of Aqueous Humor Uncovers Glutathione and Energy Metabolites as Key Biomarkers of Myopia Progression

Breaking: Metabolic Profiling of Aqueous Humor Identifies new Biomarkers Linked to Myopia Progression

Valencia, December 16 – A multinational collaboration has unveiled a extensive map of the eye’s aqueous humor metabolism across different myopia levels, spotlighting glutathione and several energy-related metabolites as potential biomarkers of the myopic eye. The findings suggest that myopia is not solely driven by oxidative stress but also by shifts in cellular metabolism, opening doors to novel diagnostics and therapies.

Researchers from a specialized ocular diseases group at a Valencia-based university, in partnership with the University of Valencia, Incliva, and the Institute of Retina and Ocular Diseases, conducted a detailed metabolomic study in patients undergoing cataract surgery. The work examined individuals with high myopia, low myopia, and non-myopic controls, aiming to clarify how metabolic changes relate to disease progression.

What the study did

In the first phase,116 patients underwent metabolic profiling of the aqueous humor using nuclear magnetic resonance (NMR). The team identified 59 metabolites and detected 31 major differences between groups, many of which aligned with known markers of oxidative stress in myopic eyes.

In a second phase, involving 73 patients, researchers observed important shifts in the balance between reduced and oxidized glutathione across all groups. Glutathione’s primary role as a cellular antioxidant was emphasized as a key indicator of oxidative stress within the eye and its link to myopia progression.

Key takeaways

Experts say the complete metabolic map of the aqueous humor highlights potential biomarkers that could underpin new diagnostic tools and metabolomics-based therapies for myopia. This study also provides the first strong evidence of notable glutathione variations between high myopia, low myopia, and non-myopic eyes, reinforcing the view that oxidative stress plays a central role in the condition’s progression.

The research team notes that these findings build on earlier metabolomic work, which first revealed metabolic differences between high and low myopia.The published results,led by principal investigators from CEU UCH and collaborating centers,bolster the case for metabolomics as a path toward targeted interventions for myopia management.

Context and significance

Myopia currently affects about a quarter of the global population and could rise to nearly 50% by 2050. In cases of high myopia, degenerative changes in the back of the eye can occur, sometimes leading to blindness. By mapping the aqueous humor’s metabolic landscape, researchers hope to identify early biomarkers and therapeutic targets before irreversible damage develops.

Study details and publication

The work was conducted by the Physio-Pathological and Protective Mechanisms of Ocular Diseases group at the CEU UCH,in collaboration with researchers from the University of Valencia,Incliva,and the Institute of Retina and Ocular Diseases of Valencia. The study has been published in the journal Antioxidants and was led by CEU UCH researchers Salvador Mérida and Francisco bosch, among others.

Key facts at a glance

Aspect	Finding	Group/Participants
Metabolites identified	59 distinct metabolites	116 patients (Phase 1)
Major metabolite differences	31 significant differences	Phase 1
Glutathione variations	Significant changes in reduced vs. oxidized forms	phase 2; 73 patients
Technique	NMR metabolomics of aqueous humor	Phase 1 & 2
Institutions	CEU UCH, University of Valencia, Incliva, Institute of retina and Ocular Diseases	Collaborative study

Evergreen insights for the long term

The study’s metabolomic approach could reshape how eye diseases associated with myopia are diagnosed and treated. By identifying early biomarkers in the aqueous humor,clinicians may develop targeted interventions that address both oxidative stress and metabolic imbalances. Over time, these findings could inspire non-invasive surrogate markers and personalized therapies that slow or halt myopia progression, reducing the risk of vision-threatening complications for millions worldwide.

As metabolomics methods advance, expect broader submission to other ocular conditions where metabolism and oxidative stress intersect. interdisciplinary collaboration between ophthalmology, biochemistry, and systems medicine will be crucial to translate these biomarkers into practical clinical tools.

Two questions for readers

1) Do you think metabolic biomarkers could become a routine part of myopia screening in the near future?

2) What are the ethical and practical considerations of sampling ocular fluids for diagnostic purposes, and how might alternatives evolve?

Disclaimer: This article reports on scientific research and is not medical advice. For personal health concerns, consult a qualified professional.

Share your thoughts and join the discussion below.

**Mechanistic Insight**

Metabolic Mapping Techniques for Aqueous Humor

Sample acquisition and processing

1. Aqueous humor aspiration – performed under sterile conditions during routine intra‑ocular surgery (e.g., cataract extraction) to obtain 100‑200 µL of fluid.
2. Immediate quenching – samples mixed on ice with cold methanol (1:3 v/v) to halt enzymatic activity and preserve redox status.

Analytical platforms

• Liquid chromatography‑tandem mass spectrometry (LC‑MS/MS) – high‑resolution, targeted quantification of glutathione, ATP/ADP/AMP, and TCA‑cycle intermediates.
• Nuclear magnetic resonance (NMR) spectroscopy – untargeted profiling for detecting low‑abundance metabolites (e.g., succinate, fumarate).
• Hybrid approaches – combined LC‑MS/NMR pipelines enhance coverage of both polar and non‑polar compounds, increasing biomarker finding power.

Recent meta‑analysis (Zhang et al., 2023) reports a 27 % increase in metabolite detection when integrating LC‑MS with NMR for ocular fluids.

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Core Metabolites Linked to Myopia Progression

Metabolite	Functional class	Observed trend in myopic eyes	Key references
Reduced glutathione (GSH)	Antioxidant / redox buffer	↓ 30 % relative to emmetropic controls	Wang et al., 2024
Oxidized glutathione (GSSG)	oxidative stress marker	↑ 45 %	Wang et al., 2024
ATP	Cellular energy	↓ 22 %	Li & Chen, 2023
ADP / AMP	Energy charge	↑ 15 % (ADP), ↑ 18 % (AMP)	Li & Chen, 2023
Lactate	Glycolytic end‑product	↑ 35 %	Sun et al., 2023
Citric‑acid cycle intermediates (α‑KG, succinate)	Mitochondrial metabolism	Variable; α‑KG ↓ 12 %, succinate ↑ 9 %	Sun et al., 2023

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Glutathione as a Redox Biomarker

• Mechanistic insight – GSH maintains lens transparency and retinal health by scavenging reactive oxygen species (ROS). Depletion triggers oxidative damage to scleral fibroblasts, accelerating axial elongation.
• correlation with axial length – Cross‑sectional data show a negative Pearson coefficient (r = ‑0.62, p < 0.001) between aqueous GSH concentration and axial length in children aged 6‑12 years.
• Predictive value – A logistic regression model incorporating GSH/GSSG ratio yields an AUC of 0.87 for distinguishing progressive myopia (> 0.5 D/year) from stable cases.

Practical tip for clinicians

• Incorporate point‑of‑care GSH assays (e.g., fluorometric kits) into routine refraction follow‑up for high‑risk pediatric patients. Early detection of GSH depletion can guide antioxidant therapy before significant refractive shift.

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Energy Metabolite Shifts in Myopic Eyes

1. Glycolytic up‑regulation – Elevated lactate and decreased ATP suggest a shift toward anaerobic metabolism in the retina and choroid.
2. Mitochondrial stress – Increased ADP/AMP ratios indicate compromised oxidative phosphorylation, corroborated by reduced mitochondrial DNA copy number in scleral tissue (Zhou et al., 2024).
3. TCA‑cycle remodeling – Altered α‑ketoglutarate and succinate levels reflect a rewired citric‑acid cycle, possibly to support rapid extracellular matrix remodeling during axial growth.

Bullet‑point summary of metabolic consequences

• ↑ Lactate → local acidification, promoting scleral collagen degradation.
• ↓ ATP → impaired Na⁺/K⁺‑pump function, affecting ocular fluid dynamics.
• ↑ AMP/ADP ratio → activation of AMP‑activated protein kinase (AMPK), which modulates growth‑factor signaling pathways implicated in myopia.

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Clinical Relevance of Biomarker Panels

Risk stratification algorithm (validated in a multicenter cohort,n = 842)

1. Measure aqueous GSH/GSSG ratio and ATP/AMP ratio.
2. Assign points:

• GSH/GSSG < 0.5 → 2 points
• ATP/AMP < 1.2 → 1 point
• Lactate > 2.5 mmol/L → 1 point
• score ≥ 3 predicts ≥ 0.75 D/year progression over 12 months (sensitivity = 84 %, specificity = 78 %).

Implementation checklist for eye clinics

• ☐ Ensure sterile aqueous sampling protocol during scheduled surgery.
• ☐ Use standardized LC‑MS/MS calibration curves for quantification.
• ☐ Integrate biomarker scores into electronic health records (EHR) for automated alerts.

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Translational Applications & Real‑World Evidence

Antioxidant supplementation trial (NCT05874321)

• Design: Double‑blind, randomized, 200 children (8‑12 y) with low GSH levels received oral N‑acetylcysteine (600 mg/day) vs placebo for 12 months.
• Outcome: Mean myopic shift reduced by 0.42 D in the treatment arm (p < 0.01); aqueous GSH increased by 27 % (p < 0.001).

Metabolic modulator case study

• Patient: 14‑year‑old female with progressive myopia (+ 3.75 D) and documented ATP deficiency.
• Intervention: Oral riboflavin (400 mg/day) for 6 months to support mitochondrial complex I function.
• Result: Stabilization of refractive error (≤ 0.25 D change) and normalization of ATP/AMP ratio on follow‑up metabolomics.

These examples demonstrate that targeted metabolic correction can alter the natural course of myopia, reinforcing the clinical utility of aqueous‑humor biomarkers.

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Future Directions in Myopia Metabolomics

• Longitudinal metabolomic profiling – Serial aqueous sampling at 6‑month intervals to map dynamic biomarker trajectories and refine predictive models.
• Integrative omics – Combine metabolomics with transcriptomics (e.g., scleral fibroblast RNA‑seq) to uncover upstream regulatory networks driving glutathione depletion and energy dysregulation.
• Artificial intelligence – Deploy machine‑learning classifiers (random forest, gradient boosting) on multi‑modal datasets to improve early‑stage detection accuracy beyond 90 % AUC.
• Non‑invasive surrogate biomarkers – Explore tear‑film metabolite signatures that reflect aqueous‑humor glutathione and energy status, facilitating routine screening without intra‑ocular access.

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