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Opacity of the lens caused by cataracts could lead to severe visual impairment and even blindness. Oxidative stress caused by exposure of lens epithelial cells to hydrogen peroxide (H2O2) can lead to DNA damage and impair cell function. Therefore, how to prevent lens epithelial cells from being harmed by H2O2 is an urgent problem. The ZNF219 gene belongs to the Kruppel like zinc finger gene family, which is involved in a variety of biological processes. In this study, we found the low expression of ZNF219 in H2O2-induced HLE-B3 cells. We further noticed ZNF219 could improve the survival rate of H2O2-induced HLE-B3 cells, and inhibit the apoptosis and oxidative stress response. Mechanically, ZNF219 protected human lens epithelial cells against H2O2-induced injury via targeting SOX9 through activating AKT/GSK3β pathway. We therefore thought ZNF219 was a key protective protein in the oxidative damage of human lens epithelial cells and the pathogenesis of cataract. [ABSTRACT FROM AUTHOR]