Folic acid prevents inner hair cell degeneration via genomic stability

Damage to inner hair cells (IHCs) is a leading cause of hearing loss, typically initiating at the base region of the basilar membrane. However, the mechanisms and preventative strategies for IHC damage remain to be elucidated. This study revealed that IHCs in the low-frequency region exhibit a significantly faster calcium clearance rate than high-frequency IHCs. This difference is associated with different PMCA1 expression. We then generated an IHC-specific Pmca1 knockout mouse model (Pmca1 CKO) exhibiting profound hearing loss and IHC death. Using single-cell RNA-seq analysis, we found that the differentially expressed genes (DEGs) were related to tetrahydrofolate biosynthesis, DNA damage, and DNA repair dysfunction. We therefore treated Pmca1 CKO mice with folic acid and found that it protected IHCs by reducing γ-H2A.X levels. In addition, we found that folic acid protected IHCs from noise-induced damage. Overall, our findings suggest that disrupted calcium homeostasis plays a role in IHC damage and that folic acid may be a promising therapeutic agent for protecting hair cells.