Schisantherin B Alleviates Cisplatin-Induced Hearing Loss via CNPY2 Coordination
Cisplatin-induced hearing loss (CIHL), is characterized by irreversible hearing impairment and no effective interventions, is a major chemotherapy side effect. Schisantherin B (STB), a natural compound isolated from Schisandra chinensis, have been shown to possess neuroprotective and hepatoprotective properties, whereas research in the auditory field is limited. This study alleviates cisplatin-mediated auditory toxicity in vitro and successfully rescued auditory brainstem response (ABR) thresholds in a CIHL model of adult albino guinea pigs by protecting hair cells, synaptic ribbons and spiral ganglion neurons. The drug affinity responsive target stability (DARTS) assay, the cellular thermal shift assay (CETSA), and the surface plasmon resonance (SPR) assay have determined that the canopy FGF signaling regulator 2 (CNPY2) protein, a key initiator of ER stress, is an important partner of STB, inhibiting downstream signals PERK/CHOP signals and endoplasmic reticulum (ER) stress-induced apoptosis. The collective findings of this study demonstrate that STB is a promising candidate drug for protecting against CIHL. Moreover, the results indicate that CNPY2 primed ER stress is a critical biological process for STB-mediated oto-protection. Overall design: RNA-seq profiling of cochlears from guinea pigs following treatment with cisplatin, cisplatin plus STB and wildtype.