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

Siwei Guo; Jieying Cao; Guodong Hong; Yuning Song; Ming Xia; Peipei Li; Wei Yuan; Yu Xiao; Guoqiang Sun; Shuang Liu; Shengda Cao; Jieyu Qi; Xiuli Bi; Ziyi Liu; Yunhao Wu; Wen Li; Xiaoxu Zhao; Jiangang Gao; Renjie Chai; Xiaolong Fu

doi:10.1038/s43587-025-00860-y

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

Siwei Guo
, Jieying Cao
, Guodong Hong
, Yuning Song
, Ming Xia
, Peipei Li
, Wei Yuan
, Yu Xiao
, Guoqiang Sun
, Shuang Liu
, Shengda Cao
, Jieyu Qi
, Xiuli Bi
, Ziyi Liu
, Yunhao Wu
, Wen Li
, Xiaoxu Zhao
, Jiangang Gao^*
, Renjie Chai^*
, Xiaolong Fu^*

^*Corresponding author for this work

Shandong University
Shandong First Medical University & Shandong Academy of Medical Sciences
Chongqing General Hospital
CAS - Institute of Zoology
Shandong Normal University
Qilu Hospital of Shandong University
Beijing Institute of Technology
Southeast University, Nanjing
Nantong University
University of Electronic Science and Technology of China
Southeast University Shenzhen Research Institute

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

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.

Original language	English
Article number	121
Pages (from-to)	848-867
Number of pages	20
Journal	Nature Aging
Volume	5
Issue number	5
DOIs	https://doi.org/10.1038/s43587-025-00860-y
Publication status	Published - May 2025
Externally published	Yes

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Guo, S., Cao, J., Hong, G., Song, Y., Xia, M., Li, P., Yuan, W., Xiao, Y., Sun, G., Liu, S., Cao, S., Qi, J., Bi, X., Liu, Z., Wu, Y., Li, W., Zhao, X., Gao, J., Chai, R., & Fu, X. (2025). mRNA metabolism regulator human antigen R (HuR) regulates age-related hearing loss in aged mice. Nature Aging, 5(5), 848-867. Article 121. https://doi.org/10.1038/s43587-025-00860-y

@article{8f0bec8a70ab44078046870595398a27,

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

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.",

author = "Siwei Guo and Jieying Cao and Guodong Hong and Yuning Song and Ming Xia and Peipei Li and Wei Yuan and Yu Xiao and Guoqiang Sun and Shuang Liu and Shengda Cao and Jieyu Qi and Xiuli Bi and Ziyi Liu and Yunhao Wu and Wen Li and Xiaoxu Zhao and Jiangang Gao and Renjie Chai and Xiaolong Fu",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.",

year = "2025",

month = may,

doi = "10.1038/s43587-025-00860-y",

language = "English",

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T1 - mRNA metabolism regulator human antigen R (HuR) regulates age-related hearing loss in aged mice

AU - Guo, Siwei

AU - Cao, Jieying

AU - Hong, Guodong

AU - Song, Yuning

AU - Xia, Ming

AU - Li, Peipei

AU - Yuan, Wei

AU - Xiao, Yu

AU - Sun, Guoqiang

AU - Liu, Shuang

AU - Cao, Shengda

AU - Qi, Jieyu

AU - Bi, Xiuli

AU - Liu, Ziyi

AU - Wu, Yunhao

AU - Li, Wen

AU - Zhao, Xiaoxu

AU - Gao, Jiangang

AU - Chai, Renjie

AU - Fu, Xiaolong

PY - 2025/5

Y1 - 2025/5

N2 - 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.

AB - 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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DO - 10.1038/s43587-025-00860-y

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EP - 867

JO - Nature Aging

JF - Nature Aging

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M1 - 121

ER -

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

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