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

Nature Aging volume 5, pages 848–867 (2025)Cite this article

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An Author Correction to this article was published on 08 July 2025

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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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Fig. 1: Dynamics of HuR expression in the cochlea.
Fig. 2: HuR is a negative regulator of ARHL.
Fig. 3: HuR is essential for the maintenance of hearing function.
Fig. 4: Neonatal overexpression of HuR can partially rescue hearing function in Atoh1-HuR−/− and Pax2-HuR−/− mice.
Fig. 5: Sensory HC bundle patterning in HuR-deficient mice.
Fig. 6: Altered expression of tip proteins in HuR-deficient mice.
Fig. 7: HuR targets and stabilizes Gnai3 mRNA.
Fig. 8: Neonatal overexpression of Gnai3 leads to delayed hearing loss in HuR-deficient mice.

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Data availability

The raw data of the RNA Immunoprecipitation sequencing analysis have been deposited in the Sequence Read Archive (https://www.ncbi.nlm.nih.gov/sra), under accession code PRJNA1221523. Raw data of RNA sequencing have been deposited in the Sequence Read Archive under accession codes PRJNA1221644. Source data are provided with this study. All other data are available from the corresponding authors upon request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant nos. 82322019 to F.X.L., 82192863 to G.J.G., 82271175 to F.X.L., 82001204 to C.R.J., 82301320 to L.P.P., 82201294 to B.X.L., 82201296 to L.W., 82301305 to L.Z.Y., 82330033 to C.R.J., 82030029 to C.R.J. and 92149304 to C.R.J.). National Key R&D Program of China (grant nos. 2021YFA1101300 to F.X.L., 2021YFA1101800 to C.R.J. and 2020YFA0112503 to C.R.J.). The Natural Science Foundation from Shandong Province (grant nos. ZR2022QH338 to L.Z.Y., ZR2021QH269 to L.W. and ZR2022QH205 to B.X.L.). Natural Science Foundation of Jiangsu Province (grant nos. BK20232007 to C.R.J.), Science and Technology Department of Sichuan Province (grant nos. 2021YFS0371 to C.R.J.), Shenzhen Science and Technology Program (grant nos. JCYJ20190814093401920 to C.R.J. and JCYJ20210324125608022 to C.R.J.), 2022 Open Project Fund of Guangdong Academy of Medica Sciences (grant no. YKY-KF202201 to C.R.J.). We acknowledge the support of the Medical Science and Technology Innovation Center at Shandong First Medical University for valuable expertise and advice on the fluorescent imaging assays by confocal microscope.

Author information

Authors and Affiliations

  1. School of Life Science, Shandong University, Qingdao, China

    Siwei Guo, Yuning Song, Peipei Li, Yu Xiao & Jiangang Gao

  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

    Siwei Guo, Jieying Cao, Guodong Hong, Ming Xia, Yu Xiao, Xiuli Bi, Ziyi Liu, Yunhao Wu, Wen Li, Xiaoxu Zhao, Jiangang Gao & Xiaolong Fu

  3. Chongqing General Hospital, Chongqing, China

    Wei Yuan

  4. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

    Guoqiang Sun

  5. The Key Laboratory of Animal Resistant Biology of Shandong Province, College of Life Science, Shandong Normal University, Jinan, China

    Shuang Liu

  6. Department of Otorhinolaryngology, Qilu Hospital of Shandong University, NHC Key Laboratory of Otorhinolaryngology, Shandong University, Jinan, China

    Shengda Cao

  7. Department of Neurology, Aerospace Center Hospital, School of Life Science, Beijing Institute of Technology, Beijing, China

    Jieyu Qi & Xiaolong Fu

  8. 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

    Renjie Chai

  9. Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China

    Renjie Chai

  10. Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China

    Renjie Chai

  11. Southeast University Shenzhen Research Institute, Shenzhen, China

    Renjie Chai

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Contributions

X.F., R.C. and J.G. designed and supervised the research. S.G. and X.F. wrote the paper. S.G., J.C., G.H., Y.S. and P.L. performed the experiments. M.X., W.Y., G.S., J.Q., Y.X., S.L. and S.C. contributed to the materials and analyzed the data. X.B., Z.L., Y.W., W.L. and X.Z. provided technical support for this research.

Corresponding authors

Correspondence to Jiangang Gao, Renjie Chai or Xiaolong Fu.

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The authors declare no competing interests.

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Nature Aging thanks Shintaro Iwasaki and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

https://www.ncbi.nlm.nih.gov/sra/PRJNA1221523

Extended Data Fig. 1: Quantitative analysis of HuR protein expression in the cochlear HCs of young and aged mice and Macaca fascicularis.
Extended Data Fig. 1: Quantitative analysis of HuR protein expression in the cochlear HCs of young and aged mice and Macaca fascicularis.
Full size image

a, Representative fluorescence images of HuR in the SV of 1-month-old and 12-month-old mice. Scale bar, 10 μm. b, Representative fluorescence images of HuR in the SGN of 1-month-old and 12-month-old mice. Scale bars, 20 μm. c, Representative fluorescence images of HuR in the SCs of 1-month-old and 12-month-old mice. Scale bars, 10 μm. d, The fluorescence ratio of HuR signals in the cytoplasm and nucleus in Fig. 1k. The fluorescence intensity was quantified using Image J (NIH). n = 5 mice. e, Corresponding line intensity measurements for HuR protein and DAPI expression indicated that HuR is expressed only in the nucleus of HCs in young mice (1-month-old), while a portion of the HuR protein is shuttled to the cytoplasm of the HCs in aged mice (12-month-old). The fluorescence intensity was quantified using ImageJ (NIH). f, HuR immunostaining in the cochlea of young and old Macaca fascicularis. Scale bars, 20 μm. g, The fluorescence ratio of HuR signals in the cytoplasm and nucleus in (f). The fluorescence intensity was quantified using ImageJ (NIH). n = 5 Macaca fascicularis. h, Corresponding line intensity measurements for HuR protein and DAPI expression indicated that HuR is expressed only in the nucleus of OHCs in young Macaca fascicularis, while a portion of the HuR protein is shuttled to the cytoplasm of the OHCs in aged Macaca fascicularis. The fluorescence intensity was quantified using ImageJ (NIH). The data are presented as the mean ± standard error of the mean. The P-values were determined by a two-tailed t-test.

Source data

Extended Data Fig. 2 Inhibition of HuR shuttling to the cytoplasm in mouse models and successful overexpression of HuR in hair cells.

a, Western blot analysis and quantification of p53 and p21 expression (relative to GAPDH) in the cochlea of 1-month-old (1M) and 5-month-old (5M) SAMP8 mice (n = 3 mice). b, Real-time PCR analysis of p16, p21, and p53 mRNA expression (relative to β-actin) in the cochlea of 1-month-old (1M) and 5-month-old (5M) SAMP8 mice (n = 3 mice). c, The corresponding line intensity measurements show HuR protein and DAPI expression in the 1-month-old (1M), 2-month-old (2M), and 5-month-old (5M) SAMP8 mice. d, The fluorescence ratio of HuR signal between the cytoplasm and nucleus in 1-month-old (1M), 2-month-old (2M), and 5-month-old (5M) SAMP8 mice. The fluorescence intensity was quantified using ImageJ (NIH). n = 5 mice. e, HuR immunostaining in the cochlea of SAMP8 mice and SAMP8 mice injected at P50 with HuR translocation inhibitor SRI-42127. Scale bars, 10 μm. f, The corresponding line intensity measurements show HuR protein and DAPI expression in the control (CON) and SRI-42127-treated (SRI-42127) groups. g–h, The fluorescence ratio of HuR signal between the cytoplasm and nucleus in control and SRI-42127-treated groups. The fluorescence intensity was quantified using ImageJ (NIH). n = 5 mice. i, Comparison of transduction efficiency between AAV-ie-control and AAV-ie-HuR based on HA (green) and Phalloidin (red) immunostaining. Both AAV-ie-control and AAV-ie-HuR were found to efficiently transduce SCs and HCs throughout the cochlea. Scale bar, 50 μm. j,k, Histograms showing the percentage of HA-labeled SCs and HCs. n = 5 mice. The data are presented as the mean ± standard error of the mean. The P-values were determined by a two-tailed t-test in a, b, g, h, i and j, and a one-way ANOVA followed by Tukey’s multiple comparison test in d.

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Extended Data Fig. 3 Lack of HuR leads to profound hering loss due to HC defects.

a, Representative H&E staining images of HCs, SGNs, and the SV in the middle turns of cochleae from WT and HuR-deficient (Atoh1-HuR−/− and Pax2-HuR−/−) mice. Scale bar, 50 μm. b,c, Graphs illustrating the average numbers of SGNs (b) and average thickness (c) of the SV in WT and HuR-deficient mice (Atoh1-HuR−/− and Pax2-HuR−/−). n = 5 mice. d, Whole-mount IF staining of the OC from P60 and P90 WT and HuR-deficient (Atoh1-HuR−/− and Pax2-HuR−/−) mice. Phalloidin (F-actin, red); Myo7A (HCs, green). Scale bar, 50 μm. n = 7 mice. e,f, Percentage of OHCs loss in P60 (e) and P90 (f) WT and HuR-deficient (Atoh1-HuR−/− and Pax2-HuR−/−) mice. n = 7 mice. g, TUNEL analysis of the OHCs in WT, Atoh1-HuR−/− and Pax2-HuR−/− cochlea at P60. Scale bar, 50 μm. h, The mean number of TUNEL-positive OHCs. n = 10 mice. The data are presented as the mean ± standard error of the mean. The P-values were determined by a one-way ANOVA followed by Tukey’s multiple comparison test.

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Extended Data Fig. 4 HuR knockout in supporting cochlear cells does not affect hearing.

a, Schematic diagram of the transgenic HuR conditional knockout mice (Sox2-HuR−/−). b, IF staining for HuR expression in the SCs in P40 Sox2-HuR−/− mice. The white asterisks indicate supporting cells not labeled by the HuR antibody. Scale bar, 50 μm. c,d, Western blot analysis and quantification of HuR expression in the cochlea of Sox2-HuR−/− and WT mice. n = 3 mice. e, ABR thresholds of the WT and Sox2-HuR−/− mice at P60. n = 5 mice. The data are presented as the mean ± standard error of the mean. The P-values were determined by a two-tailed t-test.

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Extended Data Fig. 5 Successful overexpression of HuR in HuR-deficient mouse models.

a, Comparison of Anc80L65-control and Anc80L65-HuR transduction efficiency based on HA (green) and Myo7 (red) immunostaining. Both Anc80L65-control and Anc80L65-HuR constructs were found to efficiently transduce HCs throughout the cochlea. Scale bar, 50 μm. b,c, Histograms showing the percentage of HA-labeled IHCs and OHCs (n = 8 mice for CON; n = 10 mice for Atoh1-HuR−/− and Pax2-HuR−/−). The data are presented as the mean ± standard error of the mean. The P-values were determined by a one-way ANOVA followed by Tukey’s multiple comparison test.

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Extended Data Fig. 6 MET activity is affected in HuR mutant mice.

a, Representative images of cochlear ribbon synapses in WT and HuR-deficient mice (Atoh1-HuR−/− and Pax2-HuR−/−). The pre-synaptic (CtBP2, red) and post-synaptic (GluR2, green) markers are both immunolabeled. Scale bar, 20 μm. b, The number of ribbon synapses (CtBP2+ and GluR2+) per IHC. n = 5 mice. c, FM1-43 uptake in P60 cochlea derived from WT, Atoh1-HuR−/−, and Pax2-HuR−/− mice. HCs from WT mice displayed robust FM1-43 uptake, whereas those from both Atoh1-HuR−/− and Pax2-HuR−/− mice displayed weak FM1-43 uptake. Scale bar, 20 μm. d, FM1-43 signal intensity was measured using ImageJ. n = 5 mice, 2 images per mouse. Each value represents the average of all cells within each image. The shaded bands are presented as the mean ± standard error of the mean. e, Phalloidin-labeled OHC stereocilia in P60 WT, Atoh1-HuR−/−, and Pax2-HuR−/− mice. Scale bar, 20 μm. f, The number of HCs with abnormal stereocilia in P60 WT, Atoh1-HuR−/−, and Pax2-HuR−/− mice. n = 6 mice. g, Whole-mount IF staining for KCNQ4, BK, Prestin, and Spectrin in the OC at P60 in WT and HuR conditional knockout mice (Atoh1-HuR−/− and Pax2-HuR−/−). Scale bars, 20 μm. The data are presented as the mean ± standard error of the mean. The P-values were determined by a one-way ANOVA followed by Tukey’s multiple comparison test.

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Extended Data Fig. 7 The degeneration of stereocilia in HuR-deficient mice accelerates the aging of OHCs.

a, Representative pseudo-colored scanning electron micrographs of OHC bundles from 1-month-old and 12-month-old mice. Close-up views illustrate the three full rows (tallest [magenta], middle [blue], and short [yellow]) of stereocilia in the OHC bundles. The orange arrow points to the fused stereocilia, the green arrow points to the broken stereocilia, and the magenta arrow points to internalized stereocilia. Scale bar, 2 μm. b, TEM micrographs reveal the normal morphology of P90 WT OHCs and severe degenerative changes in Atoh1-HuR−/− and Pax2-HuR−/− OHCs. In HuR-deficient mice, the number of morphologically abnormal mitochondria and lysosomes increased. The red arrows indicate abnormal mitochondria, the yellow arrows point to lysosomes. Scale bar, 10 μm. c, Representative SA-β-gal staining of the OC of the cochlea in WT and HuR-deficient mice at P80. Yellow arrows represent the SA-β-gal-positive cells. The dashed lines indicate the region of the OC where the HCs are located. Scale bar, 50 μm. d,e, Representative immunofluorescence images of p21 in the OC of WT and HuR-deficient mice at P80 and quantitative analysis (e). Scale bar, 20 μm, n = 6 mice. The white arrows represent the p21-positive cells. f,g, Representative immunofluorescence images of γ-H2A.X in the OC of WT and HuR-deficient mice at P80 and quantitative analysis (g). Scale bar, 20 μm, n = 6 mice. The white arrows represent the γ-H2A.X-positive cells. The data are presented as the mean ± standard error of the mean. The P-values were determined by a one-way ANOVA followed by Tukey’s multiple comparison test.

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Extended Data Fig. 8 Successful overexpression of Gnai3 in HuR-deficient mouse models.

a, Comparison of Anc80L65-control and Anc80L65-Gnai3 transduction efficiency based on HA (green) and Phalloidin (red) staining. Both Anc80L65-control and Anc80L65-Gnai3 were found to efficiently transduce HCs throughout the cochlea. Scale bar, 50 μm. b,c, Histograms showing the percentage of HA-labeled OHCs and IHCs. n = 8 mice. The data are presented as the mean ± standard error of the mean. The P-values were determined by a one-way ANOVA followed by Tukey’s multiple comparison test.

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Guo, S., Cao, J., Hong, G. et al. mRNA metabolism regulator human antigen R (HuR) regulates age-related hearing loss in aged mice. Nat Aging 5, 848–867 (2025). https://doi.org/10.1038/s43587-025-00860-y

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