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Fuchs endothelial corneal dystrophy (FECD) is a bilateral, hereditary syndrome characterized by progressive irreversible injury in the corneal endothelium; it is the most frequent cause for corneal transplantation worldwide. Oxidative stress induces the apoptosis of corneal endothelial cells (CECs), and has a crucial function in FECD pathogenesis. The stimulation of the adenosine A_2A receptor (A_2Ar) inhibits oxidative stress, reduces inflammation and modulates apoptosis. Polydeoxyribonucleotide (PDRN) is a registered drug that acts through adenosine A_2Ar. Thus, the goal of this study was to assess the effect of PDRN in an in vitro FECD model. Human Corneal Endothelial Cells (IHCE) were challenged with H₂O₂ (200 μM) alone or in combination with PDRN (100 μg/mL), PDRN plus ZM241385 (1 μM) as an A_2Ar antagonist, and CGS21680 (1 μM) as a well-known A_2Ar agonist. H₂O₂ reduced the cells’ viability and increased the expression of the pro-inflammatory markers NF-κB, IL-6, IL-1β, and TNF-α; by contrast, it decreased the expression of the anti-inflammatory IL-10. Moreover, the pro-apoptotic genes Bax, Caspase-3 and Caspase-8 were concurrently upregulated with a decrease of Bcl-2 expression. PDRN and CGS21680 reverted the negative effects of H₂O₂. Co-incubation with ZM241385 abolished the effects of PDRN, indicating that A_2Ar is involved in the mode of action of PDRN. These data suggest that PDRN defends IHCE cells against H₂O₂-induced damage, potentially as a result of its antioxidant, anti-inflammatory and antiapoptotic properties, suggesting that PDRN could be used as an FECD therapy.