Targeting NLRP3/caspase-1/GSDMD to treat inner ear injury from labyrinthine hemorrhage

Sudden sensorineural hearing loss (SSNHL) is a prevalent condition in otolaryngology with poorly understood mechanisms. Inner ear labyrinthine hemorrhage (IELH) is a potentially significant cause. Our study focused on the NLR family pyrin domain containing 3 (NLRP3) inflammasome activation following IELH and the protective role of the NLRP3 inhibitor CY-09. In mice with IELH, significant increases in hearing thresholds and vestibular dysfunction were observed compared to control groups. The activation of the NLRP3 inflammasome and other pro-inflammatory factors were markedly elevated, leading to potential damage in cochlear and vestibular hair cells via the Gasdermin D (GSDMD)-mediated pyroptosis pathway. Treatment with CY-09 significantly ameliorated hearing loss and vestibular dysfunction via inhibition of the NLRP3 inflammasome and associated cell pyroptosis. These results highlight the critical roles of the NLRP3 inflammasome and pyroptosis in IELH-induced SSNHL and suggest the NLRP3/caspase-1/GSDMD pathway as a therapeutic target for managing this condition. This study offers a new theoretical basis for the potential clinical management of SSNHL.