Bavachin repairs lysosomal damage and restores protein homeostasis via PITT pathway in 4-acetaminophen-induced hearing loss.

Abstract

BACKGROUND AND PURPOSE: Drug-induced hearing loss from lysosomal dysfunction and protein imbalance is an unmet medical need, as seen with 4-acetamidophenol (APAP). Currently, no effective treatment exists. This study investigates bavachin (BV), a phytoestrogen activating PPAR, against APAP-induced hearing loss and its mechanism. EXPERIMENTAL APPROACH: APAP was used to establish hearing loss models of guinea pigs and HEI-OC1 cells, respectively. Audiometry, immunofluorescence, flow cytometry, western blot and lipid mass spectrometry were used to confirm the effect of BV on APAP induced hearing loss and its possible mechanism. KEY RESULTS: Our investigations revealed that APAP exposure induces profound pathological changes in guinea pig cochlear hair cells (HCs), including disruption of intrinsic polarity distribution and disorganization of stereociliary bundles. These morphological alterations are accompanied by impaired lysosomal trafficking and consequent protein misfolding, ultimately leading to HCs loss and disarray. Parallel experiments in HEI-OC1 auditory cells demonstrate similar pathological outcomes with significant apoptotic cell death. Importantly, as mammalian HCs lack regenerative capacity, APAP-induced HC loss results in permanent hearing impairment. Notably, we identified monomeric BV, a compound derived from Psoralea corylifolia L., as a potential therapeutic agent. BV exerts potent otoprotective effects by activating the PITT pathway to repair lysosomal membrane damage, thereby restoring protein homeostasis and hair cell polarity. CONCLUSION AND IMPLICATIONS: This dual mechanism effectively prevents APAP-induced auditory damage in both cellular and animal models, positioning BV as a promising therapeutic candidate for drug-induced hearing loss through its novel lysosomal repair activity.

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