Abstract Choroideremia (CHM) is a hereditary retinal degenerative disorder characterized by progressive dysfunction of the retinal pigment epithelium (RPE) and photoreceptors with no available therapy. Despite the recognized genetic basis of CHM, the metabolic pathways driving disease progression remain poorly defined. By investigating REP-1 deficiency in CHM disease, our study reveals a previously unrecognized role for REP-1 in regulating GLUT-1 and GLUT-4 membrane trafficking, controlling glucose uptake, and reprograming mitochondrial metabolism toward lipid oxidation. This chronic metabolic shift results in reduced glycolytic flux, elevated oxidative stress, and compromised ATP production, culminating in a progressive retinal dystrophy. Notably, pharmacological restoration of GLUT trafficking via leptin administration re-established glucose uptake and mitochondrial function, rescuing cellular energetics both in vitro and in vivo. These findings establish REP-1 as a key regulator of retinal metabolic homeostasis and suggest that targeting glucose–lipid metabolic rewiring may represent a novel therapeutic strategy for CHM and related retinal dystrophies.
Buonocore et al. (Mon,) studied this question.