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Peer-reviewedCC BY 4.0JCI Insight

Heat shock pathway activation by TRC051384 protects spiral ganglion neurons from noise-induced hearing loss

  • Jintao Yu1
  • Miguel A. Ramirez1
  • Yi-Zhi Wang1
  • Seby Edassery1
  • Maxwell Shramuk2,3
  • SangEun Yeom1
  • Casey Jiaxi Li1
  • Yuvraj Joshi1
  • Mary Ann Cheatham4,5
  • Mark A. Rutherford6
  • Leah J. Welty2,3
  • Jeffrey N. Savas1,5
6 affiliations
  1. 1Department of Neurology
  2. 2Department of Psychiatry and Behavioral Sciences, and
  3. 3Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
  4. 4Department of Communication Sciences and Disorders and
  5. 5The Hugh Knowles Center for Clinical and Basic Science in Hearing and Its Disorders, Northwestern University, Evanston, Illinois, USA.
  6. 6Department of Otolaryngology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.
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Abstract

Noise-induced hearing loss (NIHL) is a major public health problem caused by damage to cochlear hair cells, synapses, and spiral ganglion neurons (SGNs). Since effective treatments are lacking, we investigated cellular stress responses induced by moderate and loud noise in a mouse model of cochlear synaptopathy. RNA-seq 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-labyrinth barrier and reached the cochlea, induced heat shock protein gene expression, and restored ubiquitin-proteasome function in SGNs. Notably, TRC051384 treatment enhanced auditory brainstem response threshold recovery, preserved Wave I amplitudes, and maintained ribbon synapse density. Together with the existing literature, these findings identify proteotoxic stress in SGNs as a contributor to noise-induced hearing loss and support pharmacological activation of HSF1 as a promising therapeutic strategy.

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Cite

BibTeXRIS
BibTeX
@article{yu2026heat,
  title = {{Heat shock pathway activation by TRC051384 protects spiral ganglion neurons from noise-induced hearing loss}},
  author = {Jintao Yu and Miguel A. Ramirez and Yi-Zhi Wang and Seby Edassery and Maxwell Shramuk and SangEun Yeom and Casey Jiaxi Li and Yuvraj Joshi and Mary Ann Cheatham and Mark A. Rutherford and Leah J. Welty and Jeffrey N. Savas},
  journal = {JCI Insight},
  year = {2026},
  month = aug,
  doi = {10.1172/jci.insight.203285},
  url = {https://doi.org/10.1172/jci.insight.203285},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Heat shock pathway activation by TRC051384 protects spiral ganglion neurons from noise-induced hearing loss
AU  - Jintao Yu
AU  - Miguel A. Ramirez
AU  - Yi-Zhi Wang
AU  - Seby Edassery
AU  - Maxwell Shramuk
AU  - SangEun Yeom
AU  - Casey Jiaxi Li
AU  - Yuvraj Joshi
AU  - Mary Ann Cheatham
AU  - Mark A. Rutherford
AU  - Leah J. Welty
AU  - Jeffrey N. Savas
PY  - 2026
DA  - 2026/08/25
JO  - JCI Insight
DO  - 10.1172/jci.insight.203285
UR  - https://doi.org/10.1172/jci.insight.203285
AB  - Noise-induced hearing loss (NIHL) is a major public health problem caused by damage to cochlear hair cells, synapses, and spiral ganglion neurons (SGNs). Since effective treatments are lacking, we investigated cellular stress responses induced by moderate and loud noise in a mouse model of cochlear synaptopathy. RNA-seq 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-labyrinth barrier and reached the cochlea, induced heat shock protein gene expression, and restored ubiquitin-proteasome function in SGNs. Notably, TRC051384 treatment enhanced auditory brainstem response threshold recovery, preserved Wave I amplitudes, and maintained ribbon synapse density. Together with the existing literature, these findings identify proteotoxic stress in SGNs as a contributor to noise-induced hearing loss and support pharmacological activation of HSF1 as a promising therapeutic strategy.
SN  - 2379-3708
ER  -