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<p>Lens Epithelial Cells (LECs) apoptosis is a critical driving factor of age-related cataract (ARC), but the specific molecular mechanisms remain undefined. Herein, a novel target of ROR1 regulation was identified, the mechanism was elucidated by which ROR1 and its associated pathway proteins influence hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>)-induced apoptosis of LECs in ARC. We found decreased ROR1 expression in human cataract lens capsules compared to normal ones, the trend was also observed in young and old mice. Experiments including CCK8, Hoechst 33,342 staining, and Western blot analysis confirmed that reduced ROR1 levels were linked to H<sub>2</sub>O<sub>2</sub>-induced apoptosis in HLEB3 cells. To investigate its effects on cell viability and apoptosis, we created a ROR1 interference plasmid and an overexpression plasmid. The overexpression of ROR1 effectively inhibited H<sub>2</sub>O<sub>2</sub>-induced apoptosis of HLEB3 cells while ROR1 knockdown lowered the viability and increased the apoptosis of HLEB3 cells. Additionally, increased P38 phosphorylation was identified as a contributor to lens epithelial cell apoptosis and ARC, with ROR1 influencing this through the phosphorylation of the P38. Similarly, the relationships between P300 and STAT3, upstream of ROR1, in apoptosis of LECs and ARC were explored, and it was found that P300 and STAT3 were negatively correlated with apoptosis of LECs and ARC. In addition, the double luciferase report showed that P300 and STAT3 synergistically up-regulated the expression of ROR1. Overall, this study demonstrates that the STAT3/ROR1/P38 pathway mitigates apoptosis of LECs in ARC progression, offering a novel strategy for ARC prevention and treatment in clinical settings.</p>

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Downregulation of RORl via STAT3 and P300 Promotes P38 Pathway- Dependent Lens Epithelial Cells Apoptosis in Age-Related Cataract

  • 期刊论文

  • 发表日期：

    2025年2月28日

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  • Yue Zhang,
  • Yuzhu Hu,
  • Dongmei Su,
  • Yanjiang Fu,
  • Xiaoya Chen,
  • Xiao Zhang,
  • Shunfei Zheng,
  • Xu Ma,
  • Shanshan Hu

摘要

Lens Epithelial Cells (LECs) apoptosis is a critical driving factor of age-related cataract (ARC), but the specific molecular mechanisms remain undefined. Herein, a novel target of ROR1 regulation was identified, the mechanism was elucidated by which ROR1 and its associated pathway proteins influence hydrogen peroxide (H2O2)-induced apoptosis of LECs in ARC. We found decreased ROR1 expression in human cataract lens capsules compared to normal ones, the trend was also observed in young and old mice. Experiments including CCK8, Hoechst 33,342 staining, and Western blot analysis confirmed that reduced ROR1 levels were linked to H2O2-induced apoptosis in HLEB3 cells. To investigate its effects on cell viability and apoptosis, we created a ROR1 interference plasmid and an overexpression plasmid. The overexpression of ROR1 effectively inhibited H2O2-induced apoptosis of HLEB3 cells while ROR1 knockdown lowered the viability and increased the apoptosis of HLEB3 cells. Additionally, increased P38 phosphorylation was identified as a contributor to lens epithelial cell apoptosis and ARC, with ROR1 influencing this through the phosphorylation of the P38. Similarly, the relationships between P300 and STAT3, upstream of ROR1, in apoptosis of LECs and ARC were explored, and it was found that P300 and STAT3 were negatively correlated with apoptosis of LECs and ARC. In addition, the double luciferase report showed that P300 and STAT3 synergistically up-regulated the expression of ROR1. Overall, this study demonstrates that the STAT3/ROR1/P38 pathway mitigates apoptosis of LECs in ARC progression, offering a novel strategy for ARC prevention and treatment in clinical settings.