Proteomic Signatures of Noise‐Induced Hearing Loss in the Mouse Cochlea

ABSTRACT Hearing loss affects over 1.5 billion people worldwide and has substantial social, educational, and economic consequences. Although genetic studies have identified numerous hearing‐loss‐associated genes, the molecular changes accompanying noise‐induced hearing loss (NIHL) remain incompletely understood. We characterized the adult mouse cochlear proteome following damaging noise exposure using nano‐LC–MS/MS and an integrative bioinformatics workflow. Comparative profiling of normal‐hearing and NIHL cochleae identified 1742 proteins and an 80‐protein NIHL‐associated signature comprising 49 quantitatively defined differentially abundant proteins and 31 condition‐specific proteins. These proteins were organized into five functional groups encompassing metabolic and mitochondrial function, protein synthesis and ribonucleoprotein complexes, structural and synaptic organization, cell polarity and cytoskeletal remodeling, and regulatory and stress‐responsive functions. Representative alterations included reduced HSPA9, a mitochondrial chaperone involved in protein homeostasis; changes in the RNA‐associated proteins PRMT1 and CIRBP; reduced HAPLN1, associated with extracellular matrix organization; and altered MAP2K2, a signaling protein related to cell polarity; and increased SYNJ2. Comparison with an independent cochlear proteomic data set identified 39 of the 80 proteins as dysregulated, with 22 showing concordant directional changes. Single‐cell transcriptomic mapping provided cellular context for 74 of the 80 protein‐associated genes, while human genetic and disease annotations supported the prioritization of selected proteins associated with hearing or ear phenotypes. Together, these findings define a proteomic landscape of the noise‐exposed cochlea and identify molecular candidates and cellular processes for further investigation of NIHL.