Abstract
(1) Aminoglycosides remain indispensable in modern medicine but share a serious dose-limiting adverse effect: irreversible cochleovestibular ototoxicity. (2) This scoping review systematically maps experimental and clinical strategies aimed at preventing aminoglycoside-induced hearing loss, integrating mechanistic insights across preclinical and translational domains. (3) Preclinical evidence, encompassing in vitro and in vivo studies, delineates three principal mechanistic ways of protection: (A) antioxidant and redox modulation, including N-acetyl-L-cysteine (NAC), vitamin C, edaravone, and selected phytochemicals, which counteract reactive oxygen species-mediated hair cell apoptosis; (B) mitochondrial stabilization with compounds such as mitoquinone, celastrol, and histone deacetylase inhibitors restoring bioenergetic and proteostatic balance; and (C) restriction of aminoglycoside entry through partial blockade of the mechano-electrical transduction channel, notably by ORC-13661 and related modulators. Additional strategies involve nitric oxide modulation, vasodilatory agents, and iron chelation. Efficacy, however, remains compound- and antibiotic-specific, with paradoxical effects observed for several drugs. Clinical evidence remains limited and methodologically diverse. Of the investigated pharmacologic interventions, aspirin provides the most robust and reproducible evidence of protection against gentamicin-induced hearing loss, whereas NAC demonstrates a consistent, but population-specific benefit among dialysis patients. In contrast, vitamin E-despite promising experimental findings-has failed to show clinically significant otoprotective effects in randomized human studies. (4) In conclusion, while experimental data establish a strong mechanistic basis for pharmacologic otoprotection, clinical studies remain few, underpowered, and methodologically inconsistent. Standardized, adequately powered, and mechanistically informed clinical trials are urgently needed to translate experimental promise into actionable otoprotective strategies.