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Since effective treatments are lacking, we investigated cellular stress responses induced by moderate and loud noise in a mouse model of cochlear synaptopathy. RNA sequencing and spatial transcriptomics revealed that noise exposure elicited a robust but transient upregulation of endoplasmic reticulum chaperones and proteasome subunits in SGNs and their supporting cells. To target this response, we administered TRC051384, a small-molecule activator of the heat shock transcription factor Hsf1, prior to noise exposure. TRC051384 crossed the blood\u2013labyrinth barrier and reached the cochlea, induced heat shock protein gene expression, and restored ubiquitin\u2013proteasome function in SGNs. Notably, TRC051384 treatment enhanced auditory brainstem response threshold recovery, preserved Wave I amplitudes, and maintained ribbon synapse density. These findings establish proteotoxic stress in SGNs as a key driver of NIHL and identify HSF1 activation as a promising therapeutic strategy.<\/jats:p>","DOI":"10.64898\/2025.12.08.693048","type":"posted-content","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T14:55:13Z","timestamp":1765464913000},"source":"Crossref","is-referenced-by-count":2,"title":["Heat-shock pathway activation by TRC051384 protects spiral ganglion neurons from noise-induced hearing loss"],"prefix":"10.64898","author":[{"given":"Jintao","family":"Yu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miguel A.","family":"Ramirez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-Zhi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seby","family":"Edassery","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maxwell","family":"Shramuk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary Ann","family":"Cheatham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark A.","family":"Rutherford","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leah J","family":"Welty","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey N","family":"Savas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025121310150786000_2025.12.08.693048v1.1","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.113-a34"},{"issue":"9","key":"2025121310150786000_2025.12.08.693048v1.2","first-page":"2749","article-title":"Noise-induced hearing loss","volume":"61","year":"2000","journal-title":"Am Fam Physician"},{"key":"2025121310150786000_2025.12.08.693048v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.aap.2008.05.013"},{"key":"2025121310150786000_2025.12.08.693048v1.4","doi-asserted-by":"publisher","DOI":"10.4103\/1463-1741.45308"},{"key":"2025121310150786000_2025.12.08.693048v1.5","doi-asserted-by":"publisher","DOI":"10.3109\/00016487909126417"},{"key":"2025121310150786000_2025.12.08.693048v1.6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1746-1561.2007.00197.x"},{"key":"2025121310150786000_2025.12.08.693048v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/scientificamerican0815-48"},{"key":"2025121310150786000_2025.12.08.693048v1.8","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0782-16.2016"},{"issue":"7","key":"2025121310150786000_2025.12.08.693048v1.9","doi-asserted-by":"crossref","first-page":"2192","DOI":"10.1016\/j.bbagen.2014.04.005","article-title":"Time evolution of noise induced oxidation in outer hair cells: role of NAD(P)H and plasma membrane fluidity","volume":"1840","year":"2014","journal-title":"Biochim Biophys Acta"},{"key":"2025121310150786000_2025.12.08.693048v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2006.10.006"},{"issue":"3","key":"2025121310150786000_2025.12.08.693048v1.11","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s10162-014-0441-4","article-title":"Antioxidants reduce cellular and functional changes induced by intense noise in the inner ear and cochlear nucleus","volume":"15","year":"2014","journal-title":"J Assoc Res Otolaryngol"},{"key":"2025121310150786000_2025.12.08.693048v1.12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1805223116"},{"key":"2025121310150786000_2025.12.08.693048v1.13","doi-asserted-by":"publisher","DOI":"10.1097\/01.moo.0000186799.45377.63"},{"issue":"70","key":"2025121310150786000_2025.12.08.693048v1.14","doi-asserted-by":"crossref","first-page":"149","DOI":"10.4103\/1463-1741.134915","article-title":"Protective effect of unilateral and bilateral ear plugs on noise-induced hearing loss: functional and morphological evaluation in animal model","volume":"16","year":"2014","journal-title":"Noise Health"},{"key":"2025121310150786000_2025.12.08.693048v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2011.07.002"},{"key":"2025121310150786000_2025.12.08.693048v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2017.01.003"},{"key":"2025121310150786000_2025.12.08.693048v1.17","doi-asserted-by":"publisher","DOI":"10.1007\/s101620020028"},{"key":"2025121310150786000_2025.12.08.693048v1.18","doi-asserted-by":"crossref","unstructured":"Song Q , Shen P , Li X , Shi L , Liu L , Wang J , et al. 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