| Title: | Erythropoiesis-inosine metabolic axis failure underlying retinal neurodegeneration in glaucoma: novel diagnoses and therapies |
| Journal: | Experimental & Molecular Medicine |
| Published: | 13 Feb 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41688739/ |
| DOI: | https://doi.org/10.1038/s12276-026-01654-x |
| URL: | https://www.nature.com/articles/s12276-026-01654-x.pdf |
Publication 17762
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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.</p>
12 Keywords
- Animals
- Disease Models, Animal
- Erythrocytes
- Erythropoiesis
- Female
- Glaucoma
- Humans
- Inosine
- Male
- Mice
- Retinal Degeneration
- Retinal Ganglion Cells
19 Authors
- Yuyu Chou
- Wuping Liu
- Yanxiu Li
- Changhan Chen
- Cheng Luo
- Shiping Shen
- Piaoyu Dai
- Lemeng Feng
- Wenhao Xiao
- Yiyan Wang
- Juncheng Wang
- Linlin Wan
- Zhiyu Yang
- Tingting Xie
- Yujin Zhang
- Rodney E. Kellems
- Weitao Song
- Xiaobo Xia
- Yang Xia
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