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<p>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 (<i>n</i> = 127,028) and validating our findings in an independent clinical cohort (<i>n</i> = 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>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月13日

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  • 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

摘要

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.