2. Academic Validation
  3. DLK/JNK3 Upregulation Aggravates Hair Cell Senescence in Mice Cochleae via Excessive Autophagy

DLK/JNK3 Upregulation Aggravates Hair Cell Senescence in Mice Cochleae via Excessive Autophagy

  • Aging Cell. 2025 May 12:e70099. doi: 10.1111/acel.70099.
Rui Ding 1 2 3,  Weiyi Huang 1 2 3,  Chenling Shen 1 2 3,  Yi Pan 1 2 3,  Yiming Zhong 1 2 3 4,  Bing Kong 1 2 3,  Yilin Shen 1 2 3,  Mingliang Xiang 1 2 3 4,  Bin Ye 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Otolaryngology & Head and Neck Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China.
  • 3 Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Department of Audiology & Speech-Language Pathology, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
PMID: 40356329 DOI: 10.1111/acel.70099
Abstract

Cell death mediated by the abnormal activation of Autophagy has been observed in many neurodegenerative diseases. Dual leucine zipper kinase (DLK), a member of the mitogen-activated protein kinase cascade, plays a key role in regulating cellular Autophagy and the progression of neurodegenerative diseases. However, its role in age-related hearing loss has not been reported. In this study, we found that DLK, phosphorylated c-Jun N-terminal kinase (p-JNK), and JNK3 expression increased in the cochleae of C57BL/6J mice during aging. The DLK/JNK pathway and Autophagy are excessively activated in the House Ear Institute-Organ of Corti 1 (HEI-OC1) senescent hair cell line. After DLK was upregulated in HEI-OC1 cells, Autophagy was activated, and cell aging was initiated. Inhibiting the DLK/JNK pathway in senescent HEI-OC1 cells can reduce Autophagy activation and senescence, and inhibiting Autophagy activation can also alleviate senescence. The inhibition of DLK or JNK3 in vivo significantly reduced age-related cochlear structural damage and hearing loss in C57BL/6J mice. The results of the present study showed that DLK/JNK3 may play a key role in cochlear hair cell senescence and age-related hearing loss through the abnormal activation of Autophagy within cochlear hair cells, suggesting that DLK or JNK3 may be potential targets for alleviating age-related hearing loss.

Keywords

age‐related hearing loss; autophagy; hair cell senescence; mitogen‐activated protein kinase; ubiquitin‐proteasome system.

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