Prestin as a context-dependent biomarker of outer hair cell stress: Integrating preclinical and clinical evidence

A BSTRACT The early detection of hearing loss remains a major clinical challenge. In many patients, once functional changes become evident on pure-tone audiometry, their recovery is limited. Outer hair cells (OHCs) are essential for cochlear amplification, and their injury is a common pathway in many forms of sensorineural hearing loss. However, reliable biomarkers that reflect hearing impairment in real-time are still lacking. Prestin, a motor protein located in the lateral membrane of OHCs, has been proposed as a potential marker of cochlear stress, but findings across studies vary, and its clinical significance remains uncertain. In this review, we re-examine current evidence to determine under which biological and clinical conditions serum prestin provides meaningful information. We examined data from models of cisplatin exposure, aminoglycoside ototoxicity, noise injury, cyclodextrin-related stress, and age-related hearing loss, along with available human studies. In acute injury models, circulating prestin often shows a transient increase during early OHC membrane damage, suggesting that it reflects active cellular stress. In contrast, chronic degenerative conditions and aging are associated with reduced cochlear prestin expression, which represents a gradual loss of OHC reserve rather than ongoing membrane injury. Differences in assay platforms, isoform detection, and sampling timing may contribute to inconsistent findings. Overall, prestin should not be viewed as a marker of hearing loss severity. Rather, it may indicate acute OHC membrane stress in specific contexts. When interpreted according to etiology and timing, it may help identify early cochlear stress and may support earlier monitoring or otoprotective intervention in selected settings.