International Journal of Immunopathology and Pharmacology · 2 authors, 2 centres
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This study found that Sestrin 2 (SESN2) is downregulated in cataract lens tissue and protects human lens epithelial cells from hydrogen peroxide-induced damage. Upregulation of SESN2 reduced apoptosis, oxidative stress, and inflammation by activating the mTOR/Nrf2 signaling pathway. These findings suggest SESN2 as a potential therapeutic target for cataract prevention and treatment.
**Background:** Cataract is a leading cause of blindness worldwide, with oxidative stress-induced apoptosis of lens epithelial cells (LECs) being a key pathogenic mechanism. Sestrin 2 (SESN2) is a stress-induced protein with antioxidant and cytoprotective properties, but its role in cataract was unknown. This study aimed to investigate the effect of SESN2 on hydrogen peroxide (H2O2)-induced damage in human LECs and explore the underlying molecular mechanisms involving the mTOR/Nrf2 pathway.
**Methods:** Clinical anterior lens capsule samples were obtained from 25 cataract patients (grade III cortical cataract, 14 male, 11 female, aged 50–61 years) and 15 normal controls (9 male, 6 female, aged 43–59 years) undergoing eyeball enucleation. The human LEC line SRA01/04 was treated with 200 μM H2O2 for 24 h to induce oxidative stress. SESN2 expression was modulated using pcDNA-SESN2 (overexpression) or si-SESN2 (knockdown). Cell viability was assessed by CCK-8 assay, apoptosis by flow cytometry, and protein expression by Western blot. Oxidative stress markers (SOD, CAT, MDA, ROS) were measured using commercial kits, and inflammatory cytokines (IL-1β, IL-18, TNF-α) by ELISA. Bioinformatics analysis using CTD and STITCH databases identified the mTOR pathway as a target of SESN2. To confirm pathway involvement, cells were treated with rapamycin (50 nM, mTOR inhibitor) or co-transfected with si-Nrf2 (Nrf2 knockdown).
**Key Results:** SESN2 mRNA and protein were significantly lower in cataract lens tissue compared to normal controls (p < 0.01). In SRA01/04 cells, H2O2 treatment increased SESN2 expression in a dose- and time-dependent manner, with maximal expression at 200 μM for 24 h. Overexpression of SESN2 significantly improved cell viability (p < 0.01), reduced apoptosis (p < 0.01), decreased Bax and increased Bcl-2 expression (p < 0.01), enhanced SOD and CAT activity, and reduced MDA and ROS levels (p < 0.01). It also suppressed H2O2-induced increases in IL-1β, IL-18, and TNF-α (p < 0.01). Conversely, SESN2 knockdown exacerbated all these effects. H2O2 reduced phosphorylation of mTOR and p70S6K, while SESN2 overexpression restored their phosphorylation (p < 0.01). Rapamycin treatment reversed the protective effects of SESN2, reducing cell viability, increasing apoptosis, and worsening oxidative stress and inflammation (p < 0.05 to p < 0.01). H2O2 increased Nrf2 protein expression, and SESN2 overexpression further enhanced Nrf2 levels (p < 0.01). Knockdown of Nrf2 abrogated SESN2-mediated protection, reducing cell viability, increasing apoptosis, decreasing SOD activity, and elevating MDA and inflammatory cytokines (p < 0.05 to p < 0.01).
**Clinical Implications:** This study demonstrates that SESN2 protects human LECs from oxidative stress, apoptosis, and inflammation by activating the mTOR/Nrf2 signaling pathway. The downregulation of SESN2 in cataract tissue suggests its deficiency may contribute to cataract pathogenesis. These findings provide a novel molecular target for pharmacological prevention or treatment of cataract, potentially reducing the need for surgery. However, the study is limited to in vitro experiments and small clinical samples; in vivo animal studies and clinical trials are needed to validate these results and assess therapeutic feasibility.