Berberrubine protects against noise-induced cochlear damage and hearing loss by inhibiting the p38 MAPK signaling pathway

Cochlear hair cells are critical sensory receptors for auditory function, and exposure to high-intensity noise can lead to irreversible hearing loss. However, the mechanisms underlying noise-induced hearing loss (NIHL) are poorly understood, and effective therapeutic strategies have yet to be developed. In this study, berberrubine (BB) was found to protect HEI-OC1 cells and hair cells of cochlear explants from hydrogen peroxide (H₂O₂)-induced damage. Furthermore, BB pretreatment protected against cochlear damage and preserved hearing in a mouse model of NIHL. Structural analysis using hematoxylin–eosin and immunofluorescence staining showed that BB pretreatment effectively protected structures such as the ribbon synapses of hair cells and the stria vascularis. In addition, BB pretreatment significantly reduced 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE) levels in the cochlear hair cells following noise exposure. RNA-sequencing analyses revealed that the protective effect of BB against NIHL involved the downregulation of Traf2 and Traf6 in the MAPK signaling pathway, leading to reduced p38 phosphorylation and accumulation of the downstream stress biomarker Chop. This reduced reactive oxygen species (ROS) generation and inflammation in the cochlea of mice following noise exposure, thereby alleviating NIHL-related cochlear damage and protecting hearing function. In summary, our findings indicate that BB is an effective agent against NIHL, acting through regulation of the p38 MAPK signaling pathway to reduce ROS generation and inflammation in the cochlea, which may represent a novel preventive strategy.