{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T03:41:12Z","timestamp":1775619672687,"version":"3.50.1"},"reference-count":42,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Guangzhou basic and applied basic research foundation, China","award":["2024A04J4473"],"award-info":[{"award-number":["2024A04J4473"]}]},{"name":"Guangzhou basic and applied basic research foundation, China","award":["SL2024A03J00523"],"award-info":[{"award-number":["SL2024A03J00523"]}]},{"name":"Guangzhou basic and applied basic research foundation, China","award":["81970783"],"award-info":[{"award-number":["81970783"]}]},{"name":"Science and Technology Program of Guangzhou, China","award":["2024A04J4473"],"award-info":[{"award-number":["2024A04J4473"]}]},{"name":"Science and Technology Program of Guangzhou, China","award":["SL2024A03J00523"],"award-info":[{"award-number":["SL2024A03J00523"]}]},{"name":"Science and Technology Program of Guangzhou, China","award":["81970783"],"award-info":[{"award-number":["81970783"]}]},{"name":"National Natural Science Foundation of China","award":["2024A04J4473"],"award-info":[{"award-number":["2024A04J4473"]}]},{"name":"National Natural Science Foundation of China","award":["SL2024A03J00523"],"award-info":[{"award-number":["SL2024A03J00523"]}]},{"name":"National Natural Science Foundation of China","award":["81970783"],"award-info":[{"award-number":["81970783"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cataracts remain the leading cause of visual impairment worldwide, yet the underlying molecular mechanisms, particularly in age-related cataracts (ARCs), are not fully understood. The Notch signaling pathway, known for its critical role in various degenerative diseases, may also contribute to ARC pathogenesis, although its specific involvement is unclear. This study investigates the role of Notch signaling in regulating ferroptosis in lens epithelial cells (LECs) and its impact on ARC progression. RNA sequencing of anterior lens capsule samples from ARC patients revealed a significant downregulation of Notch signaling, coupled with an upregulation of ferroptosis-related genes. Notch1 expression decreased, while ferroptosis markers increased in an age-dependent manner. In vitro, upregulation of Notch signaling alleviated ferroptosis by decreasing ferritin heavy chain 1 (FTH1) and p53 levels while enhancing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11). Conversely, inhibition of Notch signaling exacerbated ferroptosis, as evidenced by reduced Nrf2, GPX4, and SLC7A11 expression. These findings suggest that downregulation of Notch signaling promotes ferroptosis in LECs by impairing the Nrf2\/GPX4 antioxidant pathway, thereby contributing to ARC development. This study offers new insights into ARC pathogenesis and highlights the Notch signaling pathway as a potential therapeutic target for preventing or mitigating ARC progression.<\/jats:p>","DOI":"10.3390\/ijms26010307","type":"journal-article","created":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T11:24:19Z","timestamp":1735730659000},"page":"307","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["JAG1\/Notch Pathway Inhibition Induces Ferroptosis and Promotes Cataractogenesis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7134-5338","authenticated-orcid":false,"given":"Yan","family":"Ni","sequence":"first","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"},{"name":"Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou 510033, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liangping","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"},{"name":"Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou 510033, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fanying","family":"Jiang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"},{"name":"Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou 510033, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6355-265X","authenticated-orcid":false,"given":"Mingxing","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"},{"name":"Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou 510033, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingyan","family":"Qin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"},{"name":"Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou 510033, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1016\/S0140-6736(17)30544-5","article-title":"Cataracts","volume":"390","author":"Liu","year":"2017","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/S0140-6736(22)01839-6","article-title":"Cataracts","volume":"401","author":"Cicinelli","year":"2023","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Braakhuis, A.J., Donaldson, C.I., Lim, J.C., and Donaldson, P.J. 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