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Peer-reviewedCC BY-NC-NDJournal of otology

Systematic Proteome-wide Mendelian Randomization to Identify Novel Therapeutic Targets for Age-related Hearing Loss.

  • Kun Zhang1,2
  • Zhuoyan Li1,2
  • Luyao Wang1,2
  • Xijian Xin1,2
  • Xiaodong Qiu3
  • Peng Qu4,5
  • Dingding Dong6
  • Hanbing Zhang1,2
6 affiliations
  1. 1Department of Otorhinolaryngology, Qilu Hospital of Shandong University, Jinan, Shandong, China.
  2. 2NHC Key Laboratory of Otorhinolaryngology, Shandong University, Jinan, Shandong, China.
  3. 3Department of Operating Room, Qilu Hospital of Shandong University, Jinan, Shandong, China.
  4. 4Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.
  5. 5Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
  6. 6Department of Otorhinolaryngology-Head and Neck Surgery, Qilu Hospital of Shandong University (Qingdao), Qingdao, Shandong, China.
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026systematic,
  title = {{Systematic Proteome-wide Mendelian Randomization to Identify Novel Therapeutic Targets for Age-related Hearing Loss.}},
  author = {Kun Zhang and Zhuoyan Li and Luyao Wang and Xijian Xin and Xiaodong Qiu and Peng Qu and Dingding Dong and Hanbing Zhang},
  journal = {Journal of otology},
  year = {2026},
  month = oct,
  doi = {10.26599/joto.2026.9540083},
  url = {https://europepmc.org/article/MED/42996923},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Systematic Proteome-wide Mendelian Randomization to Identify Novel Therapeutic Targets for Age-related Hearing Loss.
AU  - Kun Zhang
AU  - Zhuoyan Li
AU  - Luyao Wang
AU  - Xijian Xin
AU  - Xiaodong Qiu
AU  - Peng Qu
AU  - Dingding Dong
AU  - Hanbing Zhang
PY  - 2026
DA  - 2026/10/01
JO  - Journal of otology
DO  - 10.26599/joto.2026.9540083
UR  - https://europepmc.org/article/MED/42996923
AB  - 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.
SN  - 1672-2930
SN  - 2524-1753
ER  -