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The nuclear factor erythroid\u20102\u2010related factor 2 (Nrf2)\u2010Kelch ECH associating protein 1 (Keap1) pathway, a fundamental oxidative stress regulation mechanism, plays a crucial role in the development of cataracts. Ferulic acid (FA), recognized for its potent antioxidant properties can activate the Nrf2 signaling pathway to mitigate oxidative damage and cell apoptosis. In this study, we have demonstrated the protective effects of FA in reducing UVA\u2010induced oxidative damage and apoptosis in HLECs through the modulation of the Keap1\/Nrf2 pathway, as evidenced by both cellular and animal experiments. HLECs and Lens were exposed to 10\u2009J\/cm<jats:sup>2<\/jats:sup> UVA radiation with or without prior treatment with FA. We found that UVA radiation increased oxidative damage and cell apoptosis in HLECs, ultimately leading to opacification of rat lenses, while FA was able to attenuate both oxidative damage and cell apoptosis in HLECs and reduce the degree of lens opacification. FA upregulated the expression of antioxidant response factors of the Keap1\/Nrf2 pathway and downregulated the expression of apoptosis\u2010related genes in HLECs, as demonstrated by Western blot and RT\u2010qPCR analyses. We also found that UVA radiation increased the degree of demethylation of the Keap1 promoter in HLECs, whereas FA reduced the level of Keap1 promoter demethylation as determined by DNA sequencing. Additionally, UVA upregulated the expression of DNA active demethylase of the Keap1 promoter in HLECs, Dnmt1, Dnmt3a, and Dnmt3b, as shown by immunofluorescence, Western blot, and RT\u2010qPCR, however, FA attenuated the activity of the passive demethylase TET1 in addition to the active demethylases. These results demonstrated that UVA radiation can cause oxidative damage, cell apoptosis, and rat lens opacification by increasing the demethylation of the Keap1 promoter in lens epithelial cells. Conversely, FA was shown to reduce oxidative damage, inhibit cell apoptosis, and decrease rat lens opacification by increasing the methylation of the Keap1 promoter. These findings suggest that FA could be therapeutically beneficial in preventing and mitigating cataracts induced by UVA radiation.<\/jats:p>","DOI":"10.1002\/jbt.70031","type":"journal-article","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T12:13:57Z","timestamp":1730204037000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Ferulic Acid Protects Human Lens Epithelial Cells Against UVA\u2010Induced Oxidative Damage by Downregulating the DNA Demethylation of the Keap1 Promoter"],"prefix":"10.1002","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8017-864X","authenticated-orcid":false,"given":"Xinru","family":"Ling","sequence":"first","affiliation":[{"name":"Medical School Nanjing University Nanjing China"},{"name":"Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School Nanjing University Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Zhu","sequence":"additional","affiliation":[{"name":"Yancheng No.1 People's Hospital, Affiliated Hospital of Medical School Nanjing University Yancheng China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuling","family":"Yan","sequence":"additional","affiliation":[{"name":"Medical School Nanjing University Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haocheng","family":"Qian","sequence":"additional","affiliation":[{"name":"School of Medicine Southeast University Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen","family":"Kang","sequence":"additional","affiliation":[{"name":"Medical School Nanjing University Nanjing China"},{"name":"Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School Nanjing University Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Affiliated Jinling Hospital, Medical School of Nanjing University Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenggao","family":"Xie","sequence":"additional","affiliation":[{"name":"Medical School Nanjing University Nanjing China"},{"name":"Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School Nanjing University Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunyan","family":"Xue","sequence":"additional","affiliation":[{"name":"Medical School Nanjing University Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,10,29]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2016.05.026"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23158243"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sjbs.2021.05.071"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(20)30489-7"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu12123651"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/ICL.0b013e31821ec4f2"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00417-019-04390-3"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201903024R"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrgentox.2023.503616"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.17305\/bjbms.2010.2698"},{"key":"e_1_2_11_12_1","doi-asserted-by":"crossref","unstructured":"L. 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