Targeted Activation of OGG1 Inhibits Paraptosis in Lens Epithelial Cells of Early Age-Related Cortical Cataract

PURPOSE. To investigate potential modes of programmed cell death in the lens epithelial cells (LECs) of patients with early age-related cortical cataract (ARCC) and to explore METHODS. Anterior lens capsules were collected from early ARCC patients for comprehensive analysis. Ultrastructural examination of LECs was performed using quantified via Western blot analysis, including those for paraptosis (ALIX, GRP78), apoptosis (cleaved caspase 3 and caspase 9), pyroptosis (N-GSDMD), and ferroptosis (GPX4). Intracellular vesicle-organelle colocalization was assessed through immunofluorescence. OGG1 protein expression and activity were evaluated through multiple methods, including Western blot, laser micro-irradiation, and immunofluorescence. The therapeutic potential of the OGG1 activator TH10785 on paraptosis was investigated using an ex vivo rat lens model. RESULTS. Morphologic changes revealed significant endoplasmic reticulum (ER) swelling in ARCC patient LECs, with no characteristic apoptotic features. Paraptosis-related proteins exhibited significant alterations, while other cell death pathway markers (apoptosis, pyroptosis, and ferroptosis) remained unchanged. In the reactive oxygen species-induced paraptosis model, vesicular structures showed exclusive colocalization with ER-specific fluorescence. Elevated levels of the DNA damage marker 7,8-dihydro-8oxoguanine were observed concurrent with decreased OGG1 activity. The OGG1 activator TH10785 showed efficacy in suppressing LECs paraptosis in ex vivo rat lens cultures. CONCLUSIONS. Paraptosis was identified in the LECs of patients with early ARCC. TH10785 activates OGG1 to suppress paraptosis in LECs, suggesting a novel therapeutic approach for early ARCC intervention.