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ResearchIn-Press PreviewAgingNeuroscienceOtology Open Access | 10.1172/jci.insight.203285

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

Jintao Yu,1 Miguel A. Ramirez,1 Yi-Zhi Wang,1 Seby Edassery,1 Maxwell Shramuk,3 SangEun Yeom,1 Casey Jiaxi Li,1 Yuvraj Joshi,1 Mary Ann Cheatham,4 Mark A. Rutherford,5 Leah J. Welty,3 and Jeffrey N. Savas1

1Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, China

2Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Communication Sciences and Disorders, Northwestern University, Evanston, United States of America

5Department of Otolaryngology, Washington University in St. Louis, St. Louis, United States of America

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1Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, China

2Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Communication Sciences and Disorders, Northwestern University, Evanston, United States of America

5Department of Otolaryngology, Washington University in St. Louis, St. Louis, United States of America

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1Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, China

2Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Communication Sciences and Disorders, Northwestern University, Evanston, United States of America

5Department of Otolaryngology, Washington University in St. Louis, St. Louis, United States of America

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1Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, China

2Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Communication Sciences and Disorders, Northwestern University, Evanston, United States of America

5Department of Otolaryngology, Washington University in St. Louis, St. Louis, United States of America

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1Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, China

2Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Communication Sciences and Disorders, Northwestern University, Evanston, United States of America

5Department of Otolaryngology, Washington University in St. Louis, St. Louis, United States of America

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1Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, China

2Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Communication Sciences and Disorders, Northwestern University, Evanston, United States of America

5Department of Otolaryngology, Washington University in St. Louis, St. Louis, United States of America

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1Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, China

2Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Communication Sciences and Disorders, Northwestern University, Evanston, United States of America

5Department of Otolaryngology, Washington University in St. Louis, St. Louis, United States of America

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1Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, China

2Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Communication Sciences and Disorders, Northwestern University, Evanston, United States of America

5Department of Otolaryngology, Washington University in St. Louis, St. Louis, United States of America

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1Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, China

2Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Communication Sciences and Disorders, Northwestern University, Evanston, United States of America

5Department of Otolaryngology, Washington University in St. Louis, St. Louis, United States of America

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1Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, China

2Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Communication Sciences and Disorders, Northwestern University, Evanston, United States of America

5Department of Otolaryngology, Washington University in St. Louis, St. Louis, United States of America

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1Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, China

2Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Communication Sciences and Disorders, Northwestern University, Evanston, United States of America

5Department of Otolaryngology, Washington University in St. Louis, St. Louis, United States of America

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1Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, China

2Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

3Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Communication Sciences and Disorders, Northwestern University, Evanston, United States of America

5Department of Otolaryngology, Washington University in St. Louis, St. Louis, United States of America

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Published August 25, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.203285.
Copyright © 2026, Yu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 25, 2026 - Version history
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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 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–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 spiral ganglion neurons as a contributor to noise-induced hearing loss and support pharmacological activation of HSF1 as a promising therapeutic strategy.

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  • Version 1 (August 25, 2026): In-Press Preview
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