Retinal ALKBH5 inhibition induces myopia protection through selective regulation of ERK1/2 signaling

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BACKGROUND: Myopia has reached epidemic proportions globally with limited therapeutic targets. This study elucidated the pivotal role of retinal epitranscriptomic regulation in myopia pathogenesis, aiming to identify novel therapeutic targets for myopia control. METHODS: The study enrolled 38 myopic patients scheduled for refractive surgery to analyze peripheral blood N6-methyladenosine (m6A) levels. In parallel, we established a murine form-deprivation myopia (FDM) model to examine retinal m6A dynamics and Alkylation repair homolog protein 5 (ALKBH5) expression. Pharmacological interventions using the ALKBH5 inhibitor DDO-2728 and Extracellular signal-related kinases 1 and 2 (ERK1/2) activator Ro67-7476 were administered intravitreally. To genetically validate the role of ALKBH5, ALKBH5-knockout (ALKBH5-KO) mice were subjected to the FDM model. Comprehensive assessments included refractive measurements, retinal structure analysis, and molecular profiling of inflammatory and extracellular matrix (ECM) markers. Statistical analyses employed Pearson's correlation for clinical data and ANOVA with Tukey's post hoc tests for experimental comparisons. RESULTS: Clinical data revealed significant inverse correlations between blood m6A levels and myopia severity (refraction: r = 0.435, p < 0.01; axial length: r = -0.338, p < 0.05). FDM retinas exhibited progressive m6A reduction and specific upregulation of ALKBH5 in the ganglion cell layer (GCL), with no changes observed in other m6A regulators. Mechanistic studies demonstrated that intravitreal injection of the selective ALKBH5 inhibitor DDO-2728 (2.5 mM) effectively attenuated myopia progression, mitigated retinal thinning, suppressed inflammatory mediators, and modulated early ECM dysregulation through specific suppression of ERK1/2 hyperphosphorylation. Crucially, genetic ablation of ALKBH5 recapitulated the protective phenotype of the inhibitor, conferring significant resistance to myopia development and associated retinal pathology. Importantly, co-administration of the ERK1/2 activator Ro 67-7476 completely abolished DDO-2728's protective effects. CONCLUSIONS: Peripheral blood m6A reduction correlates with human myopia severity. Retinal ALKBH5 upregulation drives myopia progression through ERK1/2 hyperactivation. Both pharmacological inhibition and genetic deletion of ALKBH5 effectively protect against myopia, attenuate inflammatory responses, and mitigate ECM dysregulation, mechanistically linked to the suppression of ERK1/2 signaling. These findings collectively identify ALKBH5 as a novel therapeutic target and DDO-2728 as a promising strategy for myopia control.

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