Heat-Shock Pathway Activation by TRC-051384 Protects Spiral Ganglion Neurons from Noise-Induced Hearing Loss [RNA-Seq]

Noise-induced hearing loss (NIHL) is a major public health problem caused by damage to cochlear hair cells, synapses, and spiral ganglion neurons (SGNs). However, effective treatments are completely lacking. We investigated cellular stress responses induced by loud noise in a mouse model of cochlear synaptopathy and tested whether selective activation of the dominant pathway identified could confer protection. 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 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 improved auditory brainstem response recovery, preserved Wave I amplitudes, and maintained ribbon synapse density. These findings establish proteotoxic stress in SGNs as a central driver of NIHL and identify HSF1 activation as a promising therapeutic strategy.