Inhibition of Kdm2a with Daminozide suppresses high myopia progression and related neuropsychiatric comorbidities by epigenetically modulating the gut-eye axis.

Abstract

High myopia (HM) poses a growing public health challenge due to its increasing prevalence and the associated risks of blinding complications and psychological comorbidities. While traditionally considered an isolated ocular condition, emerging evidence implicates systemic mechanisms, notably through the gut-eye axis and immune factors, play important part in the pathogenesis of HM. Histone demethylase Kdm2a, the key H3K36me2 modification eraser, is critically involved in various inflammatory diseases, yet its specific role in the gut-eye axis and HM remains elusive. To address this, the HM model was successfully established. HM mice exhibited significant scleral thinning, reduced collagen protein, and prominent anxiety-like behaviors. Crucially, they were suffering from gut microbial dysbiosis and intestinal barrier impairment. Intriguingly, upregulated Kdm2a and correspondingly decreased H3K36me2 levels were observed in the intestinal epithelial cells (IECs) of HM mice. Treatment with Daminozide (DA), the selective inhibitor of Kdm2a, effectively suppressed myopia progression and ameliorated psychological comorbidities. Mechanistically, DA restored gut microbiota homeostasis, colonic morphology, and barrier integrity. The transcriptomic profiling further revealed the protective effects of Kdm2a inhibition on modulating key pathways involved in intestinal inflammation and tissue remodeling. Collectively, this work elucidates a novel gut-eye pathway in HM pathogenesis and identifies Kdm2a in IECs as a promising therapeutic target for HM and its associated psychological comorbidities.