Structure-guided mapping of ototoxicity-related proteins: drug entry, damage amplification, cell death execution, and endogenous otoprotection.

Drug-induced ototoxicity remains a clinically relevant challenge associated with the use of several essential pharmacological agents, because effective strategies to prevent permanent auditory or vestibular damage are still limited. Ototoxic drugs differ in their chemical structure, therapeutic indication, and mechanism of action, but their damaging effects converge on partially overlapping molecular events within cochlear and vestibular tissues. These events include drug access to inner-ear compartments and cellular uptake, calcium dysregulation, oxidative stress, inflammatory amplification, mitochondrial dysfunction, apoptotic execution, and the failure or insufficiency of endogenous protective responses. In this review, we organize ototoxicity-related proteins into four interconnected functional layers: drug access and entry pathways, intracellular stress amplification and damage mediation, cell death execution, and endogenous otoprotective and repair-oriented responses. For each layer, we discuss proteins with functional relevance in the inner ear, available structural information, known ligands, binding-site data, and therapeutic tractability. This structure-guided perspective highlights early entry checkpoints such as TMC1/TMC2, OCT2, CTR1, and TRPV1; damage-amplifying hubs such as NOX3, inflammatory signaling mediators, RGS17, PRMTs, and CDK2; execution mediators such as Bax, calpains, and caspases; and protective systems including HSPs, G6PD, BDNF, PINK1, KCNQ4, and sirtuins. We propose that effective otoprotection will require precise modulation rather than simple inhibition of these targets. Finally, we discuss structural druggability, delivery challenges, timing of intervention, model limitations, and target prioritization as key considerations for the rational development of precision otoprotective strategies.