Abstract
PURPOSE: To investigate whether alterations in subfoveal choroidal thickness (SFCT) and peripheral retinal refraction mediate the efficacy of repeated low-level red-light (RLRL) therapy for myopia control. METHODS: We conducted a mediation analysis within a multicenter, randomized controlled trial. A total of 300 myopic children were included in this analysis. Participants in RLRL group wore single-vision spectacles (SVSs) and received red-light therapy twice daily for 12 months. The control group wore SVSs only, without any additional myopia-control intervention. Axial length (AL), spherical equivalent refraction (SER), SFCT and total refractive difference value (TRDV) were measured at baseline and at follow-up visits over 12 months. RESULTS: After 12 months, RLRL therapy significantly attenuated axial length and myopic shift in spherical equivalence compared with controls, accompanied by sustained increases in choroidal thickness and reductions in peripheral hyperopic defocus. Mediation analysis revealed that changes in choroidal thickness and peripheral refraction accounted for 24.83% and 6.79%, respectively, of the effect on axial length inhibition, and 28.79% and 5.97% of the effect on spherical equivalent control. The remaining effects were attributable to the direct impact of red-light (68.39% for axial length and 65.24% for spherical equivalence). Notably, choroidal thickening emerged as the predominant mediator within the first three months. CONCLUSIONS: RLRL therapy exerted a predominantly direct effect on myopia control, while changes in choroidal thickness and peripheral defocus partially mediated its effectiveness. TRIAL REGISTRATION: This trial was registered at the Chinese Clinical Trial Registry on January 30, 2021, with trial registration number: ChiCTR2100042836. https://www.chictr.org.cn/showprojEN.html?proj=120971. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-07514-y.