The role of DTL in maintaining survival of cochlear hair cell and hearing function

Progressive sensorineural hearing loss is primarily driven by the progressive degeneration of cochlear hair cells (HCs); however, the detailed molecular mechanisms remain incompletely understood. This study focused on the denticleless E3 ubiquitin protein ligase homolog (DTL). Although DTL is consistently found in cochlear HCs, its specific role in hearing was unknown. DTL acts as the core substrate‑recognition subunit of the CRL4 complex, which is pivotal for maintaining genomic stability. To investigate how DTL contributes to hearing, we generated a mouse model with a conditional knockout of the Dtl gene. Auditory brain stem response testing revealed that DTL loss leads to progressive hearing loss. Specifically, ABR thresholds exhibited an initial shift at high frequencies by postnatal day 30 (P30) and progressed to severe threshold elevations across all frequencies tested by P60, accompanied by a significant reduction in wave I amplitude. DTL deficiency specifically caused progressive loss of outer hair cells, while inner hair cells were preserved. Collectively, our findings demonstrate that DTL is indispensable for HC survival by maintaining nuclear homeostasis, providing a promising target for progressive hearing loss.