Targeting prostaglandin catabolism via topical nanotherapy rescues vision in ischemic optic neuropathy
TL;DR
These findings establish 15-PGDH–mediated prostaglandin catabolism as a therapeutic target in ischemic optic neuropathy and demonstrate a clinically translatable nanotherapeutic strategy for protecting the central nervous system from ischemic neurodegeneration.
Abstract
Ischemic optic neuropathy is a leading cause of acute vision loss and currently lacks effective therapy. Here, we identify 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme responsible for prostaglandin degradation, as a metabolic checkpoint in ischemic optic neurodegeneration. Analysis of human ischemic optic nerve tissue and a murine model of optic nerve ischemia reveals marked upregulation of retinal 15-PGDH, suggesting dysregulated prostaglandin homeostasis after ischemic injury. To therapeutically target this pathway, we develop a nano-micellar formulation of the hydrophobic 15-PGDH inhibitor SW033291 (SW@NM) that enables efficient topical ocular delivery and retinal penetration. Topical administration of SW@NM suppresses retinal 15-PGDH activity, restores PGE2 levels, preserves retinal ganglion cells and optic nerve axons, and significantly improves visual function after ischemic injury. Mechanistically, 15-PGDH inhibition suppresses ferroptosis-associated lipid peroxidation and preserves mitochondrial integrity, thereby mitigating ischemia-induced neurodegeneration. Collectively, these findings establish 15-PGDH–mediated prostaglandin catabolism as a therapeutic target in ischemic optic neuropathy and demonstrate a clinically translatable nanotherapeutic strategy for protecting the central nervous system from ischemic neurodegeneration.