Erythrocyte-Targeted Therapy for Glaucoma: Neuroprotection Through Erythrocyte-Derived Sphingosine 1-Phosphate-Enhanced Fatty Acid β-Oxidation via the AMPKα-CPT1A Axis

Glaucoma is characterized by retinal ganglion cell (RGC) loss. While the role of vascular insufficiency is recognized, the specific contribution of erythrocytes has remained elusive. This study identifies a novel erythrocyte-centric pathway in glaucoma pathogenesis using integrated metabolomic, lipidomic, and functional analyses of human erythrocytes and validated mouse models. We uncover compensatory erythrocyte reprogramming: elevated intracellular bisphosphoglycerate mutase drives glycolysis toward the Rapoport-Luebering pathway to enhance oxygen release, but at the cost of pentose phosphate pathway suppression and oxidative vulnerability, which led to ROS-induced lipid peroxidation and compromise cell membrane. Concomitant L-carnitine depletion impairs the Lands cycle, failing to repair membrane sphingosine 1-phosphate (S1P) transporter MFSD2B and curtailing extracellular S1P release, yielding systemic S1P deficiency. L-carnitine supplementation emerges as a targeted erythrocyte therapy, replenishing acylcarnitine pools to restore Lands cycle flux (lysophosphatidylcholine (LPC) to phosphatidylcholine (PC) conversion) and support membrane repair of proteins like MFSD2B and GLUT1. This repair facilitates S1P release and glucose uptake, with the latter channeled into the PPP to bolster antioxidant defenses and inhibit ROS-induced lipid peroxidation, thereby preventing further membrane compromise. Extracellular S1P triggers the AMPKα-CPT1A axis to support fatty acid β-oxidation, rescuing TCA cycle, ATP levels, and cell survival of glaucoma RGCs. Integrating data from the UK Biobank and our cohort supports plasma S1P as a novel pathogenic biomarker for glaucoma, linking erythrocyte dysfunction to neurodegenerative diseases. Our work repositions erythrocytes as pivotal mediators of glaucoma, framing the glaucoma as a systemic hematologic-ophthalmic disorder and providing a translational framework for erythrocyte metabolism-targeted interventions.