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

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.