# Erythropoiesis–inosine metabolic axis failure underlying retinal neurodegeneration in glaucoma: novel diagnoses and therapies

## TL;DR

Glaucoma is redefined as a systemic metabolic disorder involving red blood cell dysfunction and inosine metabolism, offering new diagnostic and therapeutic approaches.

## Contribution

The paper identifies glaucoma as a systemic erythroid–inosine axis failure, revealing a novel metabolic pathway linking bone marrow and retinal neurodegeneration.

## Key findings

- Dyserythropoiesis and AMPK-driven erythrocyte metabolic rewiring precede glaucoma onset.
- Genetic ablation of ENT1 in mice replicates glaucoma features, including retinal hypoxia and RGC loss.
- Inosine repletion restores erythroid output and halts neurodegeneration in glaucoma models.

## Abstract

Glaucoma, long considered an ocular-limited, age-dependent and hypoxia-driven neurodegeneration, is here reframed as a systemic erythroid–inosine axis failure that originates in the bone marrow yet culminates in retinal ganglion cell (RGC) death. By mining UK Biobank datasets (n = 127,028) and validating our findings in an independent clinical cohort (n = 178), we reveal that glaucoma is preceded by dyserythropoiesis and a compensatory, AMPK-driven metabolic rewiring of mature erythrocytes that hypercatabolizes inosine to enhance oxygen unloading. This adaptation collapses when accelerated erythrocyte inosine metabolism drains systemic pools, starving high-energy demand hematopoietic progenitors, driving retinal microenvironment hypoxia and accelerating RGC loss. Genetic ablation of murine erythroid equilibrative nucleoside transporter 1 (ENT1) recapitulates the hallmark features of patients with glaucoma, including impaired erythropoiesis, reduced oxygen delivery, retinal hypoxia and RGC apoptosis in both age and intraocular pressure-induced glaucoma models. Conversely, inosine repletion reconstitutes erythroid output, restores oxygen delivery from mature erythrocytes and halts neurodegeneration in inducible glaucoma models. A ten-metabolite erythrocyte signature centered on inosine metabolism offers diagnostic potential. Altogether, our work redefines glaucoma as the first treatable systemic erythroid-driven hypoxic syndrome, positioning inosine as a pleiotropic metabolic rescue factor for neurodegeneration and a powerful biomarker for intercepting hypoxia-driven pathologies across organs.

Glaucoma is a major cause of blindness. It involves damage to the optic nerve and is often linked to high eye pressure. However, even with controlled pressure, vision can worsen. Recent studies suggest that systemic issues, such as problems with red blood cells (RBCs), might play a role. Researchers studied RBCs in patients with glaucoma to understand their role in the disease. They analyzed blood samples from patients and healthy individuals to compare RBC function and metabolism. They found that patients with glaucoma had fewer RBCs and these cells showed signs of metabolic stress. The study revealed that RBCs in patients with glaucoma have altered metabolism, relying more on a compound called inosine for energy. This change might be a response to low oxygen levels in the eye. The findings suggest that improving RBC function could help manage glaucoma.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.