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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,11,26]]},"abstract":"<jats:p>The human lens is composed of a monolayer of lens epithelial cells (LECs) and elongated fibers that align tightly but are separated by the plasma membrane. The integrity of the lens plasma membrane is crucial for maintaining lens cellular structure, homeostasis, and transparency. Glutathione peroxidase 4 (GPX4), a selenoenzyme, plays a critical role in protecting against lipid peroxidation. This study aims to elucidate the role of GPX4 in lens plasma membrane stability during lens development using in vitro, ex vivo, and in vivo systems. Our findings reveal that GPX4 deficiency triggers lens epithelial apoptosis-independent but ferroptosis-mediated cell death. Blocking lens GPX4 activity during ex vivo culture induces lens opacification, LEC death, and disruption of lens fiber cell arrangement. Deletion of lens-specific Gpx4 results in significant unsaturated phospholipid loss and an increase in oxidized phospholipids. Consequently, lenses with Gpx4 deficiency exhibit massive disruption of lens fiber cell structure, significant loss of LECs via ferroptosis, and formation of newborn cataracts. Remarkably, administering the lipid peroxidation inhibitor, liproxstatin-1, to pregnant mothers at embryonic days 9.5 significantly prevents lipid peroxidation, LEC death, and lens developmental defects. Our study unveils the crucial role of GPX4 in lens development and transparency, and also provides a successful intervention approach to prevent lens developmental defects through lipid peroxidation inhibition.<\/jats:p>","DOI":"10.1073\/pnas.2407842121","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T10:46:41Z","timestamp":1732013201000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":19,"title":["Deficiency in glutathione peroxidase 4 (GPX4) results in abnormal lens development and newborn cataract"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6530-8968","authenticated-orcid":false,"given":"Zongbo","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA 30912"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6743-6222","authenticated-orcid":false,"given":"Caili","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA 30912"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5977-6028","authenticated-orcid":false,"given":"Kazi Rafsan","family":"Radeen","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA 30912"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Aichi 464-0083, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kavitha","family":"Kettimuthu","sequence":"additional","affiliation":[{"name":"School of Medicine, Emory Integrated Metabolomics and Lipidomics Core, Emory University, Atlanta, GA 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristal","family":"Maner-Smith","sequence":"additional","affiliation":[{"name":"School of Medicine, Emory Integrated Metabolomics and Lipidomics Core, Emory University, Atlanta, GA 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5757-1109","authenticated-orcid":false,"given":"Shinya","family":"Toyokuni","sequence":"additional","affiliation":[{"name":"Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Aichi 464-0083, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6477-4465","authenticated-orcid":false,"given":"Xingjun","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA 30912"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,11,19]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2022.101112"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2004.06.003"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2016.02.011"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.3109\/10409238909086397"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2016.03.004"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.3109\/02713688409007421"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2007.04.009"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2006.07.022"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-011-9293-6"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/0925-4439(95)00091-7"},{"key":"e_1_3_4_11_2","first-page":"1053","article-title":"Age-related lipid oxidation in human lenses","volume":"39","author":"Borchman D.","year":"1998","unstructured":"D. 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