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Oxidative stress\u2010induced lens epithelial cell death plays a key role in cataract, in which ferroptosis caused by lipid peroxide accumulation and ROS overproduction has gradually widespread attention. Nevertheless, the key pathogenic factors and related molecular mechanisms remain unclear. Single\u2010cell and bulk transcriptomics analyses were conducted to characterize oxidative stress of diverse lens cell types in cataract. Lens epithelial cells were exposed to H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    to establish an oxidative stress microenvironment, and a rat cataract model was constructed by intraperitoneal injection of sodium selenite. The impact and molecular mechanisms of TIMP3 knockdown and overexpression on oxidative stress, ferroptosis, and inflammation in lens epithelial cells were investigated. Oxidative stress widely occurred in early fiber cells, fiber cells, transitional fiber cells, anterior epithelial cells, and equatorial epithelial cells in cataract lens. TIMP3\n                    <jats:sup>+<\/jats:sup>\n                    anterior epithelial cells were determined as a novel lens epithelial cell subpopulation associated with oxidative stress. The expression of TIMP3 in cataract lens was notably higher than that in normal lens. In\u00a0vitro, TIMP3 overexpression attenuated lipid peroxidation of lens epithelial cells upon H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    by elevating SOD and GSH levels, and declining ROS accumulation and BODIPY oxidation ratio. IntracellularFe\n                    <jats:sup>2+<\/jats:sup>\n                    levels, ferroptosis under the transmission electron microscope, and cytokine expression were also suppressed by TIMP3 overexpression. TIMP3 knockdown exerted the opposite effects. Mechanistically, TIMP3 overexpression inactivated Keap1 and subsequently enhanced the expression of Nrf2, HO\u20101, and GPX4 in lens epithelial cells on exposure to H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    , thus protecting lens epithelial cells from oxidative damage and ferroptosis. In\u00a0vivo, TIMP3 overexpression delayed cataract formation in rat cataract models. Our study reveals that TIMP3 suppresses oxidative damage and ferroptosis of lens epithelial cells and delays cataract formation through modulating the Keap1\/Nrf2 pathway, providing a novel antioxidative treatment strategy for cataract.\n                  <\/jats:p>","DOI":"10.1096\/fj.202501370rr","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T14:17:18Z","timestamp":1773411438000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>TIMP3<\/scp>\n                    Suppresses Oxidative Stress and Ferroptosis of Lens Epithelial Cells in Cataract Through Regulating the Keap1\/Nrf2 Pathway"],"prefix":"10.1096","volume":"40","author":[{"given":"Zhengyu","family":"Duan","sequence":"first","affiliation":[{"name":"Eye Institute and Department of Ophthalmology, Eye &amp; ENT Hospital Fudan University  Shanghai China"},{"name":"NHC Key Laboratory of Myopia Fudan University; Key Laboratory of Myopia, Chinese Academy of Medical Sciences  Shanghai China"},{"name":"Shanghai Key Laboratory of Visual Impairment and Restoration  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoxian","family":"Zhuo","sequence":"additional","affiliation":[{"name":"Eye Institute and Department of Ophthalmology, Eye &amp; ENT Hospital Fudan University  Shanghai China"},{"name":"NHC Key Laboratory of Myopia Fudan University; Key Laboratory of Myopia, Chinese Academy of Medical Sciences  Shanghai China"},{"name":"Shanghai Key Laboratory of Visual Impairment and Restoration  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Ma","sequence":"additional","affiliation":[{"name":"Eye Institute and Department of Ophthalmology, Eye &amp; ENT Hospital Fudan University  Shanghai China"},{"name":"NHC Key Laboratory of Myopia Fudan University; Key Laboratory of Myopia, Chinese Academy of Medical Sciences  Shanghai China"},{"name":"Shanghai Key Laboratory of Visual Impairment and Restoration  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixiang","family":"Hua","sequence":"additional","affiliation":[{"name":"Eye Institute and Department of Ophthalmology, Eye &amp; ENT Hospital Fudan University  Shanghai China"},{"name":"NHC Key Laboratory of Myopia Fudan University; Key Laboratory of Myopia, Chinese Academy of Medical Sciences  Shanghai China"},{"name":"Shanghai Key Laboratory of Visual Impairment and Restoration  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Han","sequence":"additional","affiliation":[{"name":"Eye Institute and Department of Ophthalmology, Eye &amp; ENT Hospital Fudan University  Shanghai China"},{"name":"NHC Key Laboratory of Myopia Fudan University; Key Laboratory of Myopia, Chinese Academy of Medical Sciences  Shanghai China"},{"name":"Shanghai Key Laboratory of Visual Impairment and Restoration  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Cai","sequence":"additional","affiliation":[{"name":"Eye Institute and Department of Ophthalmology, Eye &amp; ENT Hospital Fudan University  Shanghai China"},{"name":"NHC Key Laboratory of Myopia Fudan University; Key Laboratory of Myopia, Chinese Academy of Medical Sciences  Shanghai China"},{"name":"Shanghai Key Laboratory of Visual Impairment and Restoration  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Yang","sequence":"additional","affiliation":[{"name":"Eye Institute and Department of Ophthalmology, Eye &amp; ENT Hospital Fudan University  Shanghai China"},{"name":"NHC Key Laboratory of Myopia Fudan University; Key Laboratory of Myopia, Chinese Academy of Medical Sciences  Shanghai China"},{"name":"Shanghai Key Laboratory of Visual Impairment and Restoration  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,13]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)30544-5"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2025.1597"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(20)30488-5"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2012.07.049"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2014.12.037"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2008.01.005"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40662-021-00273-z"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaophthalmol.2021.4148"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1159\/000511456"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2022.03.015"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcrs.2018.09.022"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/09273948.2019.1687732"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202002037R"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.2174\/15672018113106660062"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2025.101224"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2022.03.009"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2020.02.027"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2023.2165323"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12886-023-03205-8"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.114048"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-025-07384-8"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2407842121"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2023.04.022"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-023-01494-6"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-018-0071-8"},{"key":"e_1_2_12_27_1","first-page":"25","article-title":"A Transcriptome Profile in Gallbladder Cancer Based on Annotation Analysis of Microarray Studies","volume":"23","author":"Ge C.","year":"2021","journal-title":"Molecular Medicine Reports"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/2419163"},{"key":"e_1_2_12_29_1","article-title":"Cell Atlas of the Human Ocular Anterior Segment: Tissue\u2010Specific and Shared Cell Types","volume":"119","author":"Zyl T.","year":"2022","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"e_1_2_12_30_1","first-page":"3573","article-title":"Integrated Analysis of Multimodal Single\u2010Cell Data","author":"Hao Y.","year":"2020","journal-title":"bioRxiv"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-019-1662-y"},{"key":"e_1_2_12_32_1","first-page":"1179","article-title":"Scater: Pre\u2010Processing, Quality Control, Normalization and Visualization of Single\u2010Cell RNA\u2010Seq Data in R","volume":"33","author":"McCarthy D. 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