Branched-chain amino acid depletion and adolescent myopia progression through mTORC1-dependent scleral remodeling

The metabolomic alterations underlying adolescent myopia progression remain unclear. In this prospective school-based cohort, 186 adolescents (93 progressors and 93 non-progressors) were followed for 12 months and randomly split into a training ( n = 150) and an internal validation set ( n = 36). Baseline serum samples were profiled using untargeted UHPLC-MS/MS. LASSO, Boruta, and RFE were used to develop a metabolite panel, which was subsequently evaluated in the internal validation set. Hartley guinea pigs ( n = 15 per group) were randomized to control, form-deprivation myopia (FDM), and three branched-chain amino acid (BCAA) dose groups (412, 2060, or 4120 mg/kg per day) and received BCAAs by oral gavage for 4 weeks. Refraction, axial length, and scleral thickness were assessed. Human scleral fibroblasts were treated with TGF-β and BCAAs, with mTORC1 or LAT1 inhibition. In the human cohort, we identified 94 endogenous differential metabolites, with BCAA-related metabolism being the most prominently perturbed. A 22-metabolite panel achieved AUROCs of 0.82 and 0.86 in the training and internal validation sets, respectively. L -leucyl- L -alanine was the strongest protective marker (OR = 0.15, 95% CI 0.04‒0.40). BCAAs attenuated axial elongation and preserved scleral thickness in FDM guinea pigs. LAT1 may be involved in BCAA-associated mTORC1 activation, whereas BCAAs may suppress TGF-β/SMAD/FOXO1-associated myofibroblast transdifferentiation. Together, these findings identify a serum metabolomic signature associated with adolescent myopia progression and an internally validated 22-metabolite panel for risk stratification that requires external validation.