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

作者：Jiru Zhu, Yutong Xia, Xiang Li, Yingying Wen, Xuhong Zhang, Le Jin, Liyue Zhang, Ziyu Wang, Yanqing Li, Xin Yu, Zhitong Chen, Jiayun Ge, Ye Shen, Jianping Tong · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-07332-2 · 被引用次数：4 · 研究领域：RNA modifications and cancer、Ubiquitin and proteasome pathways、Cancer, Hypoxia, and Metabolism

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...