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Pharmacological activation of the hypoxia-inducible factor (HIF) pathway can prevent experimental oxygen-induced retinopathy and thus has the potential to prevent blindness in 100,000 children annually. Comprehensive analysis of liver and retinal transcriptomes after HIF stabilization demonstrates that select small molecules, given systemically, protect the retina by two pathways: stimulating the liver to secrete angiogenic hepatokines or locally stimulating retinal protection. 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