{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T14:40:11Z","timestamp":1792680011212,"version":"4.5.0"},"reference-count":0,"publisher":"National Academy of Sciences","issue":"25","license":[{"start":{"date-parts":[[2023,6,16]],"date-time":"2023-06-16T00:00:00Z","timestamp":1686873600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["HL114453 U01AI156924 CA165065 NS076511"],"award-info":[{"award-number":["HL114453 U01AI156924 CA165065 NS076511"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["U01AI156923 NS061817 CA165065"],"award-info":[{"award-number":["U01AI156923 NS061817 CA165065"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004281","name":"Polish National Science Centre","doi-asserted-by":"crossref","award":["2019\/35\/D\/ST4\/02203"],"award-info":[{"award-number":["2019\/35\/D\/ST4\/02203"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["P41GM103712 P01DK096990 R01GM139297."],"award-info":[{"award-number":["P41GM103712 P01DK096990 R01GM139297."]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,6,20]]},"abstract":"<jats:p>Programmed ferroptotic death eliminates cells in all major organs and tissues with imbalanced redox metabolism due to overwhelming iron-catalyzed lipid peroxidation under insufficient control by thiols (Glutathione (GSH)). Ferroptosis has been associated with the pathogenesis of major chronic degenerative diseases and acute injuries of the brain, cardiovascular system, liver, kidneys, and other organs, and its manipulation offers a promising new strategy for anticancer therapy. This explains the high interest in designing new small-molecule\u2013specific inhibitors against ferroptosis. Given the role of 15-lipoxygenase (15LOX) association with phosphatidylethanolamine (PE)-binding protein 1 (PEBP1) in initiating ferroptosis-specific peroxidation of polyunsaturated PE, we propose a strategy of discovering antiferroptotic agents as inhibitors of the 15LOX\/PEBP1 catalytic complex rather than 15LOX alone. Here we designed, synthesized, and tested a customized library of 26 compounds using biochemical, molecular, and cell biology models along with redox lipidomic and computational analyses. We selected two lead compounds, FerroLOXIN-1 and 2, which effectively suppressed ferroptosis in\u00a0vitro and in\u00a0vivo without affecting the biosynthesis of pro-\/anti-inflammatory lipid mediators in\u00a0vivo. The effectiveness of these lead compounds is not due to radical scavenging or iron-chelation but results from their specific mechanisms of interaction with the 15LOX-2\/PEBP1 complex, which either alters the binding pose of the substrate [eicosatetraenoyl-PE (ETE-PE)] in a nonproductive way or blocks the predominant oxygen channel thus preventing the catalysis of ETE-PE peroxidation. Our successful strategy may be adapted to the design of additional chemical libraries to reveal new ferroptosis-targeting therapeutic modalities.<\/jats:p>","DOI":"10.1073\/pnas.2218896120","type":"journal-article","created":{"date-parts":[[2023,6,16]],"date-time":"2023-06-16T13:37:23Z","timestamp":1686922643000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":31,"title":["Discovering selective antiferroptotic inhibitors of the 15LOX\/PEBP1 complex noninterfering with biosynthesis of lipid mediators"],"prefix":"10.1073","volume":"120","author":[{"given":"Haider\u00a0H.","family":"Dar","sequence":"first","affiliation":[{"name":"Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolina","family":"Mikulska-Ruminska","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Faculty of Physics Astronomy and Informatics, Institute of Physics, Nicolaus Copernicus University in Toru\u0144, Toru\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0287-2091","authenticated-orcid":false,"given":"Yulia\u00a0Y.","family":"Tyurina","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane\u00a0K.","family":"Luci","sequence":"additional","affiliation":[{"name":"National Center for Advancing Translational Sciences, Rockville, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7350-1402","authenticated-orcid":false,"given":"Adam","family":"Yasgar","sequence":"additional","affiliation":[{"name":"National Center for Advancing Translational Sciences, Rockville, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5731-122X","authenticated-orcid":false,"given":"Svetlana\u00a0N.","family":"Samovich","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander\u00a0A.","family":"Kapralov","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Austin\u00a0B.","family":"Souryavong","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3474-1697","authenticated-orcid":false,"given":"Vladimir\u00a0A.","family":"Tyurin","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew\u00a0A.","family":"Amoscato","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael\u00a0W.","family":"Epperly","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galina\u00a0V.","family":"Shurin","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Standley","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodore\u00a0R.","family":"Holman","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0794-4939","authenticated-orcid":false,"given":"Claudette\u00a0M.","family":"St.\u00a0Croix","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon\u00a0C.","family":"Watkins","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew\u00a0P.","family":"VanDemark","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep","family":"Rana","sequence":"additional","affiliation":[{"name":"National Center for Advancing Translational Sciences, Rockville, MD 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11794"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7245-1885","authenticated-orcid":false,"given":"Valerian\u00a0E.","family":"Kagan","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15260"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,6,16]]},"container-title":["Proceedings of the National Academy of 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