DNA Methyltransferase Inhibitor Suppresses Corneal Scarring

Corneal fibrosis and opacity are major causes of visual impairment and blindness, while the conventional treatment by corneal transplantation remains limited due to the global shortage of donor materials and the risk of immune-mediated graft rejection. In this study, we investigated DNA methyltransferase (DNMT) inhibition using the FDA-approved agent decitabine (DAC; 5-aza-2′-deoxycytidine) to suppress corneal fibrosis. DNMT3A is a predicted target of the anti-fibrotic microRNA miR-29a, which was previously linked to the scar-reducing effects of cornealstromal stem cell-derived extracellular vesicles (doi:10.1016/j.jare.2022.05.008). DNMT3A expression was upregulated in scarred mouse corneas. In donor-derived corneal stromal fibroblasts, DAC dose-dependently suppressed TGFβ1-induced αSMA expression and attenuated myofibroblast-associated morphological and functional changes, including collagen gel contraction, at concentrations up to 50 μM. RNA sequencing further showed that DAC reversed TGFβ1-driven extracellular matrix remodeling, including changes in SPOCK1 and CTHRC1 expression. These effects were supported in injured mouse corneas, where topical DAC treatment reduced SPOCK1 and CTHRC1 expression, decreased scar formation, and restored corneal thickness toward normal levels. Fibrosis- and inflammation-associated gene expression was also downregulated, with no apparent treatment-related toxicity. In conclusion, these findings demonstrate that DNMT inhibition suppresses corneal fibrosis and myofibroblast differentiation, supporting the repurposing of DAC as a pharmacological, donor-independent strategy for reducing corneal fibrosis and preserving corneal transparency.