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 early-stage intervention strategies.

Methods: Anterior lens capsules were collected from early ARCC patients for comprehensive analysis. Ultrastructural examination of LECs was performed using transmission electron microscopy. Cell death-associated protein markers were 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-8-oxoguanine 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.