The Role of lncRNA GAS5 in Oxidative Stress and Mitochondrial Dysfunction in Age-Related Cataracts: Insights From...

This study aimed to investigate the role of lncRNA GAS5 and GADD45a in H₂O₂-induced oxidative stress and mitochondrial dysfunction in human lens epithelial cells (LECs), and to explore the underlying ceRNA mechanism involving miR-3666.

Human LECs were exposed to H₂O₂ to induce oxidative stress. The functional roles of lncRNA GAS5, miR-3666, and GADD45a were assessed using gene knockdown and overexpression experiments. Apoptosis, oxidative damage, and mitochondrial function were evaluated. In addition, anterior lens capsule tissues were collected from patients with age-related cataract and normal controls, and the expression levels of lncRNA GAS5 and GADD45a were measured to assess their correlation in clinical samples. Additionally, antisense oligonucleotides targeting lncRNA GAS5 were tested in a rat model of age-related cataract (ARC).

lncRNA GAS5 was found to act as a competing endogenous RNA that sponges miR-3666, leading to upregulation of GADD45a expression. This lncRNA GAS5/GADD45a axis increased the susceptibility of LECs to oxidative damage and apoptotic cell death. A pronounced positive association between lncRNA GAS5 and GADD45a was identified in cortical and nuclear cataracts. Inhibition of lncRNA GAS5 with antisense oligonucleotides alleviated oxidative stress in an ARC rat model.

These results reveal a novel ceRNA regulatory pathway in which lncRNA GAS5 promotes oxidative stress and apoptosis in LECs through the miR-3666/GADD45a axis, identifying lncRNA GAS5 as a potential therapeutic target for ARC treatment.