The 5-HT1A receptor antagonist WAY-100635 maleate reprograms metabolism to promote RGC differentiation and regeneration in retino-visual centers

Metabolic collapse of retinal ganglion cells (RGCs) onsets glaucoma, yet no approved drug directly protects these neurons. Through a live-cell mitochondrial screen in human stem-cell-derived hRGCs we uncovered WAY-100635 (WAY), a clinically tested 5-HT1A antagonist, as a systemic neuroprotectant. WAY triggers a reversible cyclic-AMP surge that activates PGC-1α-driven reversible mitochondrial biogenesis and suppresses apoptosis. In glaucoma associated OPTN ^E50K hRGCs, WAY restores mitochondrial fitness, dampens excitotoxicity, and reprograms metabolism toward aerobic glycolysis, while in progenitors WAY boosts mitochondrial cristae maturation, oxidative phosphorylation, and cell-cycle exit to accelerate RGC specification. Daily intraperitoneal dosing preserves RGC bodies, neural activity, promotes axon regeneration into the optic nerve and vision centers after optic-nerve crush, as well as shows RGC protection and maintenance of visual acuity in chronic ocular hypertension glaucoma. As the non-invasive neuroprotective therapy with a human safety profile, WAY addresses a critical gap in glaucoma care and potentially for other mitochondrial optic neuropathies.