Age-related cataracts are a leading cause of blindness. Previously, we have demonstrated the association of unfolded protein response with various cataractogenic stressors. However, DNA methylation alterations leading to suppression of lenticular antioxidant protection remains unclear. Here, we report the methylglyoxal-mediated sequential events responsible for Keap1 promoter DNA demethylation in human lens epithelial cells, because Keap1 is a negative regulatory protein that regulates the Nrf2 antioxidant protein. Methylglyoxal induces the ER stress and activates the unfolded protein response leading to overproduction of ROS prior to human lens epithelial cells death. Methylglyoxal also suppresses the Nrf2 and DNA methyltransferases but activates the DNA demethylation pathway enzyme, TET1. Bisulfite genomic DNA sequencing confirms the methylglyoxal-mediated Keap1 promoter DNA demethylation leading to over-expression of Keap1 mRNA and protein. Similarly, bisulfite genomic DNA sequencing of human clear lenses (n=15) slowly lose 5-methylcytosine in the Keap1 promoter throughout life, at a rate of 1% per year. By contrast, diabetic cataractous lenses (n=21) lose an average of 90% of the 5-methylcytosine regardless of the age. Over-expressed Keap1 protein is responsible for decreasing the Nrf2 by proteasomal degradation, thereby suppressing the Nrf2 dependent stress protection. This study demonstrates for the first time about the associations of unfolded protein response activation, Nrf2 dependent antioxidant system failure and loss of Keap1 promoter methylation because of altered active and passive DNA demethylation pathway enzymes in human lens epithelial cells by methylglyoxal. As an outcome, cellular redox balance is altered towards lens oxidation and cataract formation.