Age-related hearing loss is a common neurodegenerative disorder worldwide, with significant public health implications, emphasizing the urgent need for identifying novel therapeutic targets. This study seeks to uncover potential novel therapeutic targets for ARHL by employing proteome-wide Mendelian randomization analysis.

This investigation employed a proteome-wide Mendelian randomization approach, utilizing publicly accessible data from GWAS and pQTL studies. Additionally, we performed phenome-wide association studies, enrichment analysis, protein network construction, single-cell RNA sequencing analysis, colocalization analysis, drug repurposing predictions, and molecular docking simulations, all aimed at identifying more precise and targeted therapeutic strategies.

We identified six plasma proteins with genetically predicted causal effects on ARHL risk. GO analysis highlighted their predominant roles in key biological processes, including the regulation of cytosolic calcium ion concentration, negative regulation of homotypic cell-cell adhesion, and regulation of endoplasmic reticulum unfolded protein response. Additionally, important cellular components include smooth endoplasmic reticulum, and dendritic shaft. Follow-up phenome-wide association, protein network, single-cell transcriptomic, colocalization, drug repurposing, and molecular docking analyses provided convergent evidence supporting EEF2K, C1QTNF1, ATF6, JPH4, KIR2DL3, and MICB as promising therapeutic targets for ARHL, and identified four candidate compounds (Withaferin A, Cianidanol, Danthron, and adenosine triphosphate) for further therapeutic investigation.

Proteome-wide MR identified EEF2K, C1QTNF1, ATF6, JPH4, KIR2DL3, and MICB as candidate therapeutic targets for ARHL, offering new insights into target discovery. Focusing on these proteins may improve target prioritization and enhance the efficiency of drug development for ARHL.