Abstract

The actual pathways through which glucose elevation fosters the growth of diabetic cataracts (DC) are poorly comprehended. This paper demonstrates the active role played by re-programming of glutamine metabolism in facilitating ferroptosis in lens epithelial cells (LECs). Glutaminase 2 (GLS2) was found as a core in the bioinformatics analysis of diabetes and cataract -related datasets. In in-vitro tests, it was proven that high - glucose (HG) conditions trigger ferroptosis in LECs. The ferroptosis process shows features such as the loss of glutathione, over-accumulation of iron, lipid peroxidation, and mitochondrial impairment. From a mechanical point of view, HG was reported to aid in ferroptosis in LECs through a synergistic elevation of the metabolic pathway which contains glutamine transporter solute carrier family 1 member 5 (SLC1A5), GLS2, and glutamic-oxaloacetic transaminase 1 (GOT1). Genetic or pharmacological inhibition of SLC1A5, GLS2 or GOT1 was effective in preventing glutamine degradation, glutamate production and ferroptosis induced by the high-glucose-level. Connection between inhibitors and target proteins in molecular docking experiments was proven to be stable. This same metabolic response was also observed in diabetic rat lenses and showed both ferroptosis markers and epithelial destruction. This paper shows that the stimulation of ferroptosis in lens epithelial cells is triggered by high glucose through the mediation of glutamine catabolic pathway SLC1A5/GLS2/GOT1, establishing a new pathogenic pathway and a new therapeutic omission.