Targeting the ALKBH5-ERK1/2 epitranscriptomic axis: A novel therapeutic strategy for myopia intervention

Title : Targeting the ALKBH5-ERK1/2 epitranscriptomic axis: A novel therapeutic strategy for myopia intervention

Abstract:

Global myopia prevalence has reached epidemic proportions with limited therapeutic options. This study investigates retinal epitranscriptomic alterations in myopia pathogenesis through integrated clinical and experimental approaches.

Clinically, we analyzed peripheral blood N6-methyladenosine (m6A) levels in 46 implantable collamer lens (ICL) surgery patients, revealing significant inverse correlations between m6A levels and myopia severity (refraction: r = 0.421, p < 0.01; axial length: r = -0.357, p < 0.05), suggesting m6A's biomarker potential. In murine form-deprivation myopia (FDM) models, we observed specific ALKBH5 (m6A demethylase) upregulation in retinal ganglion cells accompanied by global retinal m6A hypomethylation. 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 (IL-6/8/10, MMP2, MCP-1, TGF-β1), and modulated early extracellular matrix dysregulation. These therapeutic effects were mediated through specific suppression of ERK1/2 hyperphosphorylation without altering Wnt/β-catenin signaling. Critically, co-administration of the ERK1/2 activator Ro 67-7476 completely abolished DDO-2728's protective effects. Genetic validation using ALKBH5-knockout mice subjected to FDM induction confirmed similar phenotypic protection, though with significantly reduced protective efficacy compared to pharmacological inhibition, indicating compensatory pathway activation following permanent gene ablation.

Our findings establish the ALKBH5-ERK1/2 axis as a novel therapeutic target for myopia intervention. The potent efficacy of DDO-2728 in attenuating disease progression highlights its significant translational potential for addressing the global myopia epidemic.

Biography:

She is currently a Ph.D. candidate in Ophthalmology at Zhejiang University School of Medicine (ZJUSM), under the esteemed supervision of Professor Ye Shen. Professor Shen is recognized as a pioneering figure in Asia for the introduction and development of the Implantable Collamer Lens (ICL) procedure.

Her research trajectory bridges clinical epidemiology and molecular mechanisms in myopia. During her Master's degree at ZJUSM, her primary focus was on investigating the impact of light environments on myopia epidemiology and evaluating the visual outcomes and quality following various refractive surgeries. These works provided a strong foundation in population health and clinical applications within ophthalmology.

Presently, her doctoral research delves deeper into the fundamental biology of myopia. She is dedicated to elucidating the role of retinal epigenetic alterations in the pathogenesis of myopia. Utilizing advanced molecular techniques, her work aims to uncover how epigenetic modifications within the retina contribute to the initiation and progression of myopia, seeking novel insights into its underlying mechanisms. This shift represents her commitment to understanding the root causes of this globally significant condition, complementing her prior clinical and epidemiological experience.

She is passionate about advancing ophthalmic knowledge, spanning from large-scale population studies to intricate molecular pathways, with the ultimate goal of contributing to improved strategies for myopia prevention and management.