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  2. mRNA metabolism regulator human antigen R (HuR) regulates age-related hearing loss in aged mice

mRNA metabolism regulator human antigen R (HuR) regulates age-related hearing loss in aged mice

  • Nat Aging. 2025 May;5(5):848-867. doi: 10.1038/s43587-025-00860-y.
Siwei Guo 1 2 Jieying Cao 2 Guodong Hong 2 Yuning Song 1 Ming Xia 2 Peipei Li 1 Wei Yuan 3 Yu Xiao 1 2 Guoqiang Sun 4 Shuang Liu 5 Shengda Cao 6 Jieyu Qi 7 Xiuli Bi 2 Ziyi Liu 2 Yunhao Wu 2 Wen Li 2 Xiaoxu Zhao 2 Jiangang Gao 8 9 Renjie Chai 10 11 12 13 Xiaolong Fu 14 15
Affiliations

Affiliations

  • 1 School of Life Science, Shandong University, Qingdao, China.
  • 2 Shandong Provincial Hospital, Medical Science and Technology Innovation Center, School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
  • 3 Chongqing General Hospital, Chongqing, China.
  • 4 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
  • 5 The Key Laboratory of Animal Resistant Biology of Shandong Province, College of Life Science, Shandong Normal University, Jinan, China.
  • 6 Department of Otorhinolaryngology, Qilu Hospital of Shandong University, NHC Key Laboratory of Otorhinolaryngology, Shandong University, Jinan, China.
  • 7 Department of Neurology, Aerospace Center Hospital, School of Life Science, Beijing Institute of Technology, Beijing, China.
  • 8 School of Life Science, Shandong University, Qingdao, China. jggao@sdu.edu.cn.
  • 9 Shandong Provincial Hospital, Medical Science and Technology Innovation Center, School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. jggao@sdu.edu.cn.
  • 10 State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, School of Medicine, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China. renjiec@seu.edu.cn.
  • 11 Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China. renjiec@seu.edu.cn.
  • 12 Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. renjiec@seu.edu.cn.
  • 13 Southeast University Shenzhen Research Institute, Shenzhen, China. renjiec@seu.edu.cn.
  • 14 Shandong Provincial Hospital, Medical Science and Technology Innovation Center, School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. fuxiaolong@sdfmu.edu.cn.
  • 15 Department of Neurology, Aerospace Center Hospital, School of Life Science, Beijing Institute of Technology, Beijing, China. fuxiaolong@sdfmu.edu.cn.
Abstract

Age-related hearing loss (ARHL) is among the most prevalent and complex disorders in older adults. However, the pathogenesis of ARHL remains poorly understood. Using a single-cell transcriptomic landscape of mouse cochlea at five time points (1, 2, 5, 12 and 15 months), we found that the levels of human antigen R (HuR)-a classical RNA-binding protein-increase with age. Here we show that HuR is specifically transported from the nucleus to the cytoplasm in hair cells in both aging mice and nonhuman primates. HuR overexpression in cochlea could successfully alleviate ARHL in aged mice. Meanwhile, HuR deficiency led to premature hearing dysfunction characterized by degeneration of stereocilia and the subsequent loss of hair cells. RNA immunoprecipitation Sequencing analysis revealed that HuR can bind to messenger RNAs that enable stereocilia maintenance, including Gnai3. Adeno-associated virus-mediated Gnai3 overexpression partially rescues the hearing defects in HuR-deficient mice. Taken together, these findings indicate that HuR is a potential therapeutic target for ARHL.

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