Pbx1 overexpression delays cochlear hair cells degeneration in an accelerated aging mouse model

Age-related hearing loss (ARHL), the most prevalent sensory disorder worldwide, arises primarily from cochlear hair cells (HCs) degeneration due to aging. Although the molecular mechanisms driving HC senescence are increasingly understood, effective treatments for ARHL remain lacking. This study explores the therapeutic potential role of Pre-B cell leukemia homeobox 1 (Pbx1), a transcription factor involved in inner ear development and pluripotency, in mitigating ARHL. Our results reveal a striking age-dependent reduction in PBX1 expression within mouse cochlear HCs. Using D-galactose (D-gal)/lipopolysaccharide (LPS)-induced aging models in OC-1 cells and cultured cochlear explants, we demonstrated that lentiviral and adeno-associated virus (AAV)-mediated Pbx1 overexpression significantly suppresses senescent markers and preserves HC integrity. Remarkably, in vivo delivery of Pbx1 by AAV improved auditory function and preserved HC structure and function in ARHL mouse model. These results establish Pbx1 as a key mediator of HC aging and a promising therapeutic target for ARHL. Our findings demonstrate that AAV-mediated Pbx1 overexpression represents a potential therapeutic approach to prevent ARHL progression, paving the way for future clinical management of this prevalent sensory disorder.