{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T13:41:14Z","timestamp":1776087674622,"version":"3.50.1"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T00:00:00Z","timestamp":1772755200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"content-version":"vor","delay-in-days":38,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"S&T Program of Hebei"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Brain"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Age-related hearing loss (ARHL) is a prevalent neurodegenerative condition characterized by the progressive loss of spiral ganglion neurons (SGNs). Although oxidative stress is recognized as a central pathogenic driver of ARHL, the precise molecular triggers that initiate and amplify SGN damage remain elusive. Here, we investigated the role of the Transient Receptor Potential Vanilloid 2 (TRPV2) channel in ARHL. We found that TRPV2 expression was significantly upregulated in the SGNs of aged mice, which was associated with elevated oxidative stress. Pharmacological activation of TRPV2 in 6-month-old mice (a pre-senescent stage with preserved baseline hearing) accelerated the onset of high-frequency hearing damage, as evidenced by auditory brainstem response (ABR) measurements. Consistently, TRPV2 activation exacerbated oxidative damage (assessed by 4-HNE staining) and increased apoptotic cell death (detected via TUNEL) in the SGN population. In primary SGN cultures, TRPV2 overexpression aggravated oxidative stress, whereas TRPV2 knockdown in SH-SY5Y cells (a human neuroblastoma cell line) markedly mitigated the oxidative injury as reflected by reduced 4-HNE. Our findings establish that the age-related upregulation of TRPV2 sensitizes SGNs to oxidative stress, thereby promoting neuronal damage and exacerbating ARHL. This work highlights TRPV2 as a promising therapeutic target for intervening in the progression of ARHL.<\/jats:p>","DOI":"10.1186\/s13041-026-01286-2","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T04:05:44Z","timestamp":1772769944000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Upregulation of TRPV2 exacerbates age-related hearing loss by promoting oxidative stress in spiral ganglion neurons"],"prefix":"10.1186","volume":"19","author":[{"given":"Zhidong","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huan","family":"Yin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huan","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miaomiao","family":"An","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanan","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianwang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiantao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruoxiang","family":"Miao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baoshan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,6]]},"reference":[{"key":"1286_CR1","doi-asserted-by":"crossref","unstructured":"Gates GA, Mills JH. Presbycusis. The Lancet. 2005;366:1111\u201320.","DOI":"10.1016\/S0140-6736(05)67423-5"},{"key":"1286_CR2","doi-asserted-by":"crossref","unstructured":"Englisch CN, Steinh\u00e4user J, Wemmert S, Jung M, Gawlitza J, Wenzel G et al. Immunohistochemistry reveals TRPC channels in the human hearing organ\u2014A novel ct-guided approach to the cochlea. Int J Mol Sci. 2023;24:9290.","DOI":"10.3390\/ijms24119290"},{"key":"1286_CR3","first-page":"214","volume":"68","author":"AB Zonderman","year":"2012","unstructured":"Zonderman AB, Ferrucci L. Hear Loss Incident Dement. 2012;68:214\u201320.","journal-title":"Hear Loss Incident Dement"},{"key":"1286_CR4","doi-asserted-by":"crossref","unstructured":"Keithley EM. Pathology and mechanisms of cochlear aging. J Neurosci Res. 2020;98:1674\u201384.","DOI":"10.1002\/jnr.24439"},{"key":"1286_CR5","doi-asserted-by":"crossref","unstructured":"Liu W. Regulation of spiral ganglion neuron regeneration as a therapeutic strategy in sensorineural hearing. Front Mol Neurosci. 2022;14:1\u20138.","DOI":"10.3389\/fnmol.2021.829564"},{"key":"1286_CR6","doi-asserted-by":"publisher","unstructured":"Tan WJT, Song L. Role of mitochondrial dysfunction and oxidative stress in sensorineural hearing loss. Hear Res. 2023;434:108783. https:\/\/doi.org\/10.1016\/j.heares.2023.108783","DOI":"10.1016\/j.heares.2023.108783"},{"key":"1286_CR7","doi-asserted-by":"publisher","unstructured":"Rita A, Zorzi V, Paciello F, Ziraldo G, Peres C, Raspa M et al. Redox Biology Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway. Redox Biol [Internet]. 2018;19:301\u201317. Available from: https:\/\/doi.org\/10.1016\/j.redox.2018.08.002","DOI":"10.1016\/j.redox.2018.08.002"},{"key":"1286_CR8","doi-asserted-by":"crossref","unstructured":"Peixoto Pinheiro B, M\u00fcller M, B\u00f6s M, Guezguez J, Burnet M, Tornincasa M, et al. A potassium channel agonist protects hearing function and promotes outer hair cell survival in a mouse model for age-related hearing loss. Cell Death Dis. 2022;13:595.","DOI":"10.1038\/s41419-022-04915-5"},{"key":"1286_CR9","doi-asserted-by":"crossref","unstructured":"Zhang Z, Wang B, TRP. channels in mammalian hearing loss. Front Mol Neurosci. 2025;18:1626640.","DOI":"10.3389\/fnmol.2025.1626640"},{"key":"1286_CR10","doi-asserted-by":"crossref","unstructured":"Yang S, Du Y, Li Y, Tang Q, Zhang Y, Zhao X. Tyrosine phosphorylation and palmitoylation of TRPV2 ion channel tune microglial beta- amyloid peptide phagocytosis. J Neuroinf. 2024;21:218.","DOI":"10.1186\/s12974-024-03204-6"},{"key":"1286_CR11","doi-asserted-by":"crossref","unstructured":"Zhai Q, Chen Q, Zhang N, Li H, Yu Q, Pan Y. Exploring vestibulocerebellum-vestibular nuclei-spinal trigeminal nucleus causals communication and TRPV2 ion channel in a mouse model of vestibular migraine. J Headache Pain. 2025;26(1):47.","DOI":"10.1186\/s10194-025-01986-5"},{"key":"1286_CR12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fnagi.2018.00353","volume":"10","author":"H Shen","year":"2018","unstructured":"Shen H, Liu W, Geng Q, Li H, Lu M, Liang P, et al. Age-Dependent Up-Regulation of HCN Channels in Spiral Ganglion Neurons Coincide With Hearing Loss in Mice. Front Aging Neurosci. 2018;10:1\u201311.","journal-title":"Front Aging Neurosci"},{"key":"1286_CR13","doi-asserted-by":"publisher","unstructured":"Johns JD, Adadey SM, Hoa M. The role of the stria vascularis in neglected otologic disease. Hear Res. 2023;428:108682. https:\/\/doi.org\/10.1016\/j.heares.2022.108682","DOI":"10.1016\/j.heares.2022.108682"},{"key":"1286_CR14","doi-asserted-by":"crossref","unstructured":"Yin H, Cao H, Yang J, Liu T, Li Q, Liu M, et al. FGF13 prevents age-related hearing loss by protecting spiral ganglion neurons and ribbon synapses from injury. Cell Death Discov. 2025;11:307.","DOI":"10.1038\/s41420-025-02607-5"},{"key":"1286_CR15","doi-asserted-by":"crossref","unstructured":"Zhang L, Chen S, Sun Y. Mechanism and prevention of spiral ganglion neuron degeneration in the cochlea. Front Cell Neurosci. 2022;15:1\u201313.","DOI":"10.3389\/fncel.2021.814891"},{"key":"1286_CR16","doi-asserted-by":"publisher","unstructured":"Geng Q, Li H, Zhang H, Lu M, Liu J, Wang F, et al. Association between Ca v 3 channel upregulation in spiral ganglion neurons and age-dependent hearing loss. Exp Gerontol. 2021;151:111429. https:\/\/doi.org\/10.1016\/j.exger.2021.111429","DOI":"10.1016\/j.exger.2021.111429"},{"key":"1286_CR17","doi-asserted-by":"crossref","unstructured":"Lu M, Xian F, Jin X, Hong G, Fu X, Wang S et al. Upregulation of the Ca v 1.3 channel in inner hair cells by interleukin 6- dependent inflammaging contributes to related hearing loss. Aging Cell. 2024;23(12):e14305","DOI":"10.1111\/acel.14305"},{"key":"1286_CR18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fnmol.2019.00296","volume":"12","author":"S Wang","year":"2019","unstructured":"Wang S, Geng Q, Huo L, Ma Y, Gao Y, Zhang W, et al. Transient receptor potential cation channel subfamily vanilloid 4 and 3 in the inner ear protect hearing in mice. Front Mol Neurosci. 2019;12:1\u201313.","journal-title":"Front Mol Neurosci"},{"key":"1286_CR19","doi-asserted-by":"publisher","first-page":"1340","DOI":"10.3109\/00016480902725254","volume":"129","author":"M Takumida","year":"2009","unstructured":"Takumida M, Ishibashi T, Hamamoto T, Hirakawa K, Anniko M. Age-dependent changes in the expression of klotho protein, TRPV5 and TRPV6 in mouse inner ear. Acta Otolaryngol. 2009;129:1340\u201350.","journal-title":"Acta Otolaryngol"},{"key":"1286_CR20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1096\/fj.202300457RR","volume":"37","author":"Y Zhang","year":"2023","unstructured":"Zhang Y, Lin G, Xue N, Wang Y, Du T, Liu H, et al. Differential outcomes of high-fat diet on age-related rescaling of cochlear frequency place coding. FASEB J. 2023;37:1\u201329.","journal-title":"FASEB J"},{"key":"1286_CR21","doi-asserted-by":"publisher","unstructured":"Bai Y, Liu J, Wu X, Pang B, Zhang S, Jiang M, et al. Susceptibility of immature spiral ganglion neurons to aminoglycoside-induced ototoxicity is mediated by the TRPV1 channel in mice. Hear Res. 2023;440:108910. https:\/\/doi.org\/10.1016\/j.heares.2023.108910","DOI":"10.1016\/j.heares.2023.108910"},{"key":"1286_CR22","doi-asserted-by":"crossref","unstructured":"Fricke TC, Echtermeyer F, Zielke J, De J, Filipovic MR, Claverol S. Oxidation of methionine residues activates the high- threshold heat-sensitive ion channel TRPV2. Procd Nat Acad Sci. 2019;116(48):24359\u201365.","DOI":"10.1073\/pnas.1904332116"},{"key":"1286_CR23","doi-asserted-by":"crossref","unstructured":"Li Y, Zhao T, Li J, Xia M, Li Y, Wang X et al. Review article oxidative stress and 4-hydroxy-2-nonenal (4-HNE): implications in the pathogenesis and treatment of aging-related diseases. 2022;2022:2233906.","DOI":"10.1155\/2022\/2233906"},{"key":"1286_CR24","doi-asserted-by":"crossref","unstructured":"Li D, Zhao H, Cui Z, Tian G. The role of Nrf2 in hearing loss. Front Pharmacol. 2021;12:1\u201311.","DOI":"10.3389\/fphar.2021.620921"},{"key":"1286_CR25","doi-asserted-by":"publisher","unstructured":"Li N, Yan X, Huang W, Chu M, Dong Y, Song H, et al. Curcumin protects against the age-related hearing loss by attenuating apoptosis and senescence via activating Nrf2 signaling in cochlear hair cells. Biochem Pharmacol. 2023;212:115575. https:\/\/doi.org\/10.1016\/j.bcp.2023.115575","DOI":"10.1016\/j.bcp.2023.115575"},{"key":"1286_CR26","doi-asserted-by":"publisher","unstructured":"Hoshino T, Tabuchi K, Nishimura B, Tanaka S, Nakayama M. Biochemical and biophysical research communications protective role of Nrf2 in age-related hearing loss and gentamicin ototoxicity. Biochem Biophys Res Commun. 2011;415:94\u20138. https:\/\/doi.org\/10.1016\/j.bbrc.2011.10.019","DOI":"10.1016\/j.bbrc.2011.10.019"},{"key":"1286_CR27","unstructured":"Kovalevich J, Langford D. HHS public access. 2016;9\u201321."},{"key":"1286_CR28","doi-asserted-by":"crossref","unstructured":"Rourke SAO, Shanley LC, Dunne A, Costa DL. The Nrf2-HO-1 system and in flammaging. Front Immunol. 2024;15:1457010.","DOI":"10.3389\/fimmu.2024.1457010"},{"key":"1286_CR29","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1021\/acscentsci.1c00070","volume":"7","author":"J Conde","year":"2021","unstructured":"Conde J, Pumroy RA, Baker C, Rodrigues T, Guerreiro A, Sousa BB, et al. Allosteric antagonist modulation of TRPV2 by piperlongumine impairs glioblastoma progression. ACS Cent Sci. 2021;7:868\u201381.","journal-title":"ACS Cent Sci"},{"key":"1286_CR30","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1111\/bph.17343","volume":"182","author":"M Ding","year":"2025","unstructured":"Ding M, Han R, Xie Y, Wei Z, Xue S, Zhang F, et al. Plumbagin, a novel TRPV2 inhibitor, ameliorates microglia activation and brain injury in a middle cerebral artery occlusion\/reperfusion mouse model. Br J Pharmacol. 2025;182:87\u2013103.","journal-title":"Br J Pharmacol"}],"container-title":["Molecular Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13041-026-01286-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13041-026-01286-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13041-026-01286-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T12:40:58Z","timestamp":1776084058000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13041-026-01286-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,6]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1286"],"URL":"https:\/\/doi.org\/10.1186\/s13041-026-01286-2","relation":{},"ISSN":["1756-6606"],"issn-type":[{"value":"1756-6606","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,6]]},"assertion":[{"value":"13 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All experimental procedures involving animals were approved by the Animal Care and Ethics Committee of Hebei Medical University (No.2022-AE308).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"24"}}