{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:10:42Z","timestamp":1790082642551,"version":"4.0.1"},"reference-count":62,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,13]],"date-time":"2025-07-13T00:00:00Z","timestamp":1752364800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council in Taiwan","award":["NSTC-113-2314-B-303-004"],"award-info":[{"award-number":["NSTC-113-2314-B-303-004"]}]},{"name":"National Science and Technology Council in Taiwan","award":["TTCRD 113-04"],"award-info":[{"award-number":["TTCRD 113-04"]}]},{"DOI":"10.13039\/501100005925","name":"Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation","doi-asserted-by":"publisher","award":["NSTC-113-2314-B-303-004"],"award-info":[{"award-number":["NSTC-113-2314-B-303-004"]}],"id":[{"id":"10.13039\/501100005925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005925","name":"Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation","doi-asserted-by":"publisher","award":["TTCRD 113-04"],"award-info":[{"award-number":["TTCRD 113-04"]}],"id":[{"id":"10.13039\/501100005925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Aminoglycoside antibiotics are critical in clinical use for treating severe infections, but they can occasionally cause irreversible sensorineural hearing loss. To establish a rational pathway for otoprotectant discovery, we provide an integrated, three-tier methodology\u2014comprising cell-model selection, transcriptomic analysis, and a gentamicin\u2013Texas Red (GTTR) uptake assay\u2014to guide the development of otoprotective strategies. We first utilized two murine auditory cell lines\u2014UB\/OC-2 and HEI-OC1. We focused on TMC1 and OCT2 and further explored the underlying mechanisms of ototoxicity. UB\/OC-2 exhibited a higher sensitivity to gentamicin, which correlated with elevated OCT2 expression confirmed via RT-PCR and Western blot. Transcriptomic analysis revealed upregulation of PI3K-Akt, calcium, and GPCR-related stress pathways in gentamicin-treated HEI-OC1 cells. Protein-level analysis further confirmed that gentamicin suppressed phosphorylated Akt while upregulating ER stress markers (GRP78, CHOP) and apoptotic proteins (cleaved caspase 3, PARP). Co-treatment with PI3K inhibitors (LY294002, wortmannin) further suppressed Akt phosphorylation, supporting the role of PI3K-Akt signaling in auditory cells. To visualize drug entry, we used GTTR to evaluate its applicability as a fluorescence-based uptake assay in these cell lines, which were previously employed mainly in cochlear explants. Sodium thiosulfate (STS) and N-acetylcysteine (NAC) significantly decreased GTTR uptake, suggesting a protective effect against gentamicin-induced hair cell damage. In conclusion, our findings showed a complex ototoxic cascade involving OCT2- and TMC1-mediated drug uptake, calcium imbalance, ER stress, and disruption of PI3K-Akt survival signaling. We believe that UB\/OC-2 cells serve as a practical in vitro model for mechanistic investigations and screening of otoprotective compounds. Additionally, GTTR may be a simple, effective method for evaluating protective interventions in auditory cell lines. Overall, this study provides molecular-level insights into aminoglycoside-induced ototoxicity and introduces a platform for protective strategies.<\/jats:p>","DOI":"10.3390\/ijms26146720","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T09:45:52Z","timestamp":1752572752000},"page":"6720","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Molecular Mechanisms of Aminoglycoside-Induced Ototoxicity in Murine Auditory Cells: Implications for Otoprotective Drug Development"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2588-8881","authenticated-orcid":false,"given":"Cheng-Yu","family":"Hsieh","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, Head and Neck Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427213, Taiwan"},{"name":"School of Medicine, Tzu Chi University, Hualien 970374, Taiwan"},{"name":"Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 100233, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Ni","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Head and Neck Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427213, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9932-7091","authenticated-orcid":false,"given":"Yi-Fan","family":"Chou","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Head and Neck Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427213, Taiwan"},{"name":"School of Medicine, Tzu Chi University, Hualien 970374, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan-Jen","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Head and Neck Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427213, Taiwan"},{"name":"Department of Otolaryngology, National Taiwan University Hospital, Taipei 100225, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peir-Rong","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medicine, Tzu Chi University, Hualien 970374, Taiwan"},{"name":"Department of Otolaryngology, Head and Neck Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970473, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Hsuan","family":"Wen","sequence":"additional","affiliation":[{"name":"School of Medicine, Tzu Chi University, Hualien 970374, Taiwan"},{"name":"Department of Otolaryngology, Head and Neck Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970473, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5047-2204","authenticated-orcid":false,"given":"Chen-Chi","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 100233, Taiwan"},{"name":"Department of Otolaryngology, National Taiwan University Hospital, Taipei 100225, Taiwan"},{"name":"Department of Medical Research, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu 300195, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5133-7725","authenticated-orcid":false,"given":"Chuan-Hung","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Head and Neck Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427213, Taiwan"},{"name":"School of Medicine, Tzu Chi University, Hualien 970374, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"242","DOI":"10.2471\/BLT.21.285643","article-title":"The world report on hearing, 2021","volume":"99","author":"Chadha","year":"2021","journal-title":"Bull. 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