{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T06:16:11Z","timestamp":1790403371236,"version":"4.1.0"},"reference-count":40,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2019,5,2]],"date-time":"2019-05-02T00:00:00Z","timestamp":1556755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["NRF-2015R1C1A1A01054868"],"award-info":[{"award-number":["NRF-2015R1C1A1A01054868"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Soonchunhyang University Research Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cisplatin-induced early-onset ototoxicity is linked to hearing loss. The mechanism by which cisplatin causes ototoxicity remains unclear. The purpose of this study was to identify the involvement of receptor-interacting protein kinase (RIP)3-dependent necroptosis in cisplatin-induced ototoxicity in vitro and in vivo. Sprague\u2013Dawley rats (SD, 8 week) were treated via intraperitoneal (i.p.) injection with cisplatin (16 mg\/kg for 1 day), and their hearing thresholds were measured by the auditory brainstem response (ABR) method. Hematoxylin and eosin (H &amp; E) staining, immunohistochemistry, and western blots were performed to determine the effect of cisplatin-induced ototoxicity on cochlear morphology. Inhibitor experiments with necrostatin 1 (Nec-1) and Z-VAD were also performed in HEI-OC1 cell line. H&amp;E stains revealed that the necroptotic changes were increased in the organ of Corti (OC) and spiral ganglion neurons (SGNs). Moreover, immunohistochemistry and western blot analysis showed that cisplatin treatment increased the protein levels of RIP3 in both OCs and SGNs. The treatment of Nec-1, a selective RIP1 inhibitor, resulted in markedly suppression of cisplatin-induced cell death in HEI-OC1 cells, whereas Z-VAD treatment did not change the cisplatin-induced cell death. Our results suggest that RIP3-dependent necroptosis was substantial in cisplatin-induced ototoxicity; inner cochlear regions, the OCs, and SGNs were especially sensitive to necroptosis.<\/jats:p>","DOI":"10.3390\/cells8050409","type":"journal-article","created":{"date-parts":[[2019,5,7]],"date-time":"2019-05-07T03:15:46Z","timestamp":1557198946000},"page":"409","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Cisplatin-Induced Ototoxicity in Rats Is Driven by RIP3-Dependent Necroptosis"],"prefix":"10.3390","volume":"8","author":[{"given":"Mi-Jin","family":"Choi","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, Ajou University School of Medicine, Suwon 16499, Korea"},{"name":"Bk21 Plus Research Center for Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunsook","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan 31151, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6127-7415","authenticated-orcid":false,"given":"Yun Yeong","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Ajou University School of Medicine, Suwon 16499, Korea"},{"name":"Bk21 Plus Research Center for Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oak-Sung","family":"Choo","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Ajou University School of Medicine, Suwon 16499, Korea"},{"name":"Bk21 Plus Research Center for Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1707-5714","authenticated-orcid":false,"given":"Jeong Hun","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Ajou University School of Medicine, Suwon 16499, Korea"},{"name":"Bk21 Plus Research Center for Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-Hee","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Ajou University School of Medicine, Suwon 16499, Korea"},{"name":"Bk21 Plus Research Center for Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2537-7854","authenticated-orcid":false,"given":"Jong-Seok","family":"Moon","sequence":"additional","affiliation":[{"name":"Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan 31151, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong Jun","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan 31151, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Hoon","family":"Choung","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Ajou University School of Medicine, Suwon 16499, Korea"},{"name":"Bk21 Plus Research Center for Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1038\/cdd.2009.184","article-title":"Necroptosis, necrosis and secondary necrosis converge on similar cellular disintegration features","volume":"17","author":"Vanlangenakker","year":"2010","journal-title":"Cell Death Differ."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/ncb2883","article-title":"Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis","volume":"16","author":"Cai","year":"2014","journal-title":"Nat. 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