{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T02:55:34Z","timestamp":1787626534010,"version":"build-2736575974"},"reference-count":56,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,2,15]],"date-time":"2024-02-15T00:00:00Z","timestamp":1707955200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Biomedical Advanced Research and Development Authority (BARDA)","award":["HHSO100201100029C"],"award-info":[{"award-number":["HHSO100201100029C"]}]},{"name":"Biomedical Advanced Research and Development Authority (BARDA)","award":["261201400016C-0-0-1"],"award-info":[{"award-number":["261201400016C-0-0-1"]}]},{"name":"US Department of Defense","award":["HHSO100201100029C"],"award-info":[{"award-number":["HHSO100201100029C"]}]},{"name":"US Department of Defense","award":["261201400016C-0-0-1"],"award-info":[{"award-number":["261201400016C-0-0-1"]}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["HHSO100201100029C"],"award-info":[{"award-number":["HHSO100201100029C"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["261201400016C-0-0-1"],"award-info":[{"award-number":["261201400016C-0-0-1"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fibrosis is a chronic pathology resulting from excessive deposition of extracellular matrix components that leads to the loss of tissue function. Pulmonary fibrosis can follow a variety of diverse insults including ischemia, respiratory infection, or exposure to ionizing radiation. Consequently, treatments that attenuate the development of debilitating fibrosis are in desperate need across a range of conditions. Sphingolipid metabolism is a critical regulator of cell proliferation, apoptosis, autophagy, and pathologic inflammation, processes that are all involved in fibrosis. Opaganib (formerly ABC294640) is the first-in-class investigational drug targeting sphingolipid metabolism for the treatment of cancer and inflammatory diseases. Opaganib inhibits key enzymes in sphingolipid metabolism, including sphingosine kinase-2 and dihydroceramide desaturase, thereby reducing inflammation and promoting autophagy. Herein, we demonstrate in mouse models of lung damage following exposure to ionizing radiation that opaganib significantly improved long-term survival associated with reduced lung fibrosis, suppression of granulocyte infiltration, and reduced expression of IL-6 and TNF\u03b1 at 180 days after radiation. These data further demonstrate that sphingolipid metabolism is a critical regulator of fibrogenesis, and specifically show that opaganib suppresses radiation-induced pulmonary inflammation and fibrosis. Because opaganib has demonstrated an excellent safety profile during clinical testing in other diseases (cancer and COVID-19), the present studies support additional clinical trials with this drug in patients at risk for pulmonary fibrosis.<\/jats:p>","DOI":"10.3390\/ijms25042322","type":"journal-article","created":{"date-parts":[[2024,2,15]],"date-time":"2024-02-15T11:19:01Z","timestamp":1707995941000},"page":"2322","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Sphingolipid-Modulating Drug Opaganib Protects against Radiation-Induced Lung Inflammation and Fibrosis: Potential Uses as a Medical Countermeasure and in Cancer Radiotherapy"],"prefix":"10.3390","volume":"25","author":[{"given":"Lynn W.","family":"Maines","sequence":"first","affiliation":[{"name":"Apogee Biotechnology Corporation, 1214 Research Blvd, Suite 2015, Hummelstown, PA 17036, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Staci N.","family":"Keller","sequence":"additional","affiliation":[{"name":"Apogee Biotechnology Corporation, 1214 Research Blvd, Suite 2015, Hummelstown, PA 17036, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan A.","family":"Smith","sequence":"additional","affiliation":[{"name":"Apogee Biotechnology Corporation, 1214 Research Blvd, Suite 2015, Hummelstown, PA 17036, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecelia L.","family":"Green","sequence":"additional","affiliation":[{"name":"Apogee Biotechnology Corporation, 1214 Research Blvd, Suite 2015, Hummelstown, PA 17036, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles D.","family":"Smith","sequence":"additional","affiliation":[{"name":"Apogee Biotechnology Corporation, 1214 Research Blvd, Suite 2015, Hummelstown, PA 17036, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/s41586-020-2938-9","article-title":"Fibrosis: From mechanisms to medicines","volume":"587","author":"Henderson","year":"2020","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109861","DOI":"10.1016\/j.cellsig.2020.109861","article-title":"Role of sphingosine 1-phosphate signalling in tissue fibrosis","volume":"78","author":"Donati","year":"2021","journal-title":"Cell. 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