Dual-Hit Myopia Mechanism Unveiled by Multi-Omics: Opn1mw Deficiency Primed the Retina for Exaggerated Response to Environmental Defocus.

Purpose: Chromatic cues have long been implicated in refractive development, and OPN1MW variants are strongly associated with high myopia in humans. This study aimed to elucidate how cone opsin dysfunction translates into molecular and functional susceptibility to myopia. Methods: Retinal transcriptome and metabolome sequencing were performed in Opn1mw⁻/⁻ (MKO), Opn1sw⁻/⁻ (SKO), and wild-type (WT) mice. To assess susceptibility to lens-induced myopia (LIM), the right eyes of MKO and WT mice were fitted with -25 D lenses. In a rescue experiment, MKO mice were treated with the dopamine (DA) D1 receptor agonist SKF38393 hydrochloride. Refractive error, ocular biometry, and retinal DA levels were assessed. Retinas from WT mice and MKO mice with and without lens-wearing were collected for proteomic profiling. Differentially expressed genes and proteins were analyzed by Kyoto Encyclopedia of Genes and Genomes and STRING database. Selected targets were validated by quantitative PCR and Western blotting. Results: Both MKO and SKO mice developed significant hyperopic shifts, with extensive transcriptomic and metabolic remodeling. When subjected to LIM, MKO mice exhibited exacerbated myopic shifts and lower retinal DA levels. Integrated proteomic analyses identified dopaminergic synapse-related alterations shared by Opn1mw deletion and lens-induced defocus. A convergent protein network involving TFAM, KDM5C, and SMN1, molecules linked to mitochondrial homeostasis, chromatin regulation, and RNA processing/neuronal maintenance, was consistently downregulated by M-opsin deficiency and further exacerbated by lens-induced defocus. Pharmacological activation of D1 receptors with SKF38393 attenuated LIM in MKO mice and increased TFAM and SMN1 protein levels, providing functional support for the involvement of impaired dopaminergic signaling in the enhanced myopia susceptibility of MKO mice. Conclusions: M-opsin dysfunction is associated with reduced retinal dopaminergic tone and increased susceptibility to LIM, consistent with a gene-environment dual-hit framework. A dysregulated TFAM/KDM5C/SMN1-associated molecular network may mark a vulnerable retinal state predisposing the eye to environmentally induced myopia.