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Despite recent advances in precision medicine, therapies for rarer mutations are hindered by burdensome developmental costs. To this end, Von Hippel-Lindau (VHL) is an attractive therapeutic target to treat RP. By ablating VHL in rod photoreceptors and elevating hypoxia-inducible factor (HIF) levels, we demonstrate a path to therapeutically enhancing glycolysis independent of the underlying genetic variant that slows degeneration of both rod and cone photoreceptors in a preclinical model of retinitis pigmentosa. This rod-specific intervention also resulted in reciprocal, decreased glycolytic activity within the retinal pigment epithelium (RPE) cells despite no direct genetic modifications to the RPE. Suppressing glycolysis in the RPE provided notable, noncell-autonomous therapeutic benefits to the photoreceptors, indicative of metabolically sensitive crosstalk between different cellular compartments of the retina. Surprisingly, targeting HIF2A in RPE cells did not impact RPE glycolysis, potentially implicating HIF1A as a major regulator in mouse RPE and providing a rationale for future therapeutic efforts aimed at modulating RPE metabolism.<\/jats:p>","DOI":"10.1172\/jci185796","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T12:01:09Z","timestamp":1739275269000},"source":"Crossref","is-referenced-by-count":10,"title":["Ablating VHL in rod photoreceptors modulates RPE glycolysis and improves preclinical model of retinitis pigmentosa"],"prefix":"10.1172","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1368-1178","authenticated-orcid":true,"given":"Salvatore Marco","family":"Caruso","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Columbia University, New York, New York, USA."},{"name":"Jonas Children\u2019s Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory, Institute of Human Nutrition, Columbia Stem Cell Initiative, New York, New York, USA."},{"name":"Edward S. 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