结构导向的耳毒性相关蛋白图谱：药物进入、损伤放大、细胞死亡执行与内源性耳保护

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中文摘要

药物诱导的耳毒性仍然是临床相关挑战，与多种必需药物的使用有关，因为预防永久性听觉或前庭损伤的有效策略仍然有限。耳毒性药物在化学结构、治疗适应症和作用机制上各不相同，但其损伤效应汇聚于耳蜗和前庭组织内部分重叠的分子事件。这些事件包括药物进入内耳腔室和细胞摄取、钙调节异常、氧化应激、炎症放大、线粒体功能障碍、凋亡执行以及内源性保护反应的失败或不足。在这篇综述中，我们将耳毒性相关蛋白组织为四个相互关联的功能层：药物进入和进入途径、细胞内应激放大和损伤介导、细胞死亡执行以及内源性耳保护和修复导向反应。对于每一层，我们讨论在内耳中具有功能相关性的蛋白、可用的结构信息、已知配体、结合位点数据以及治疗可及性。这种结构导向的视角突出了早期进入检查点如TMC1/TMC2、OCT2、CTR1和TRPV1；损伤放大枢纽如NOX3、炎症信号介质、RGS17、PRMTs和CDK2；执行介质如Bax、钙蛋白酶和半胱天冬酶；以及保护系统包括HSPs、G6PD、BDNF、PINK1、KCNQ4和sirtuins。我们提出有效的耳保护将需要对这些靶点进行精确调节而非简单抑制。最后，我们讨论结构可成药性、递送挑战、干预时机、模型局限性和靶点优先级，作为合理开发精准耳保护策略的关键考虑因素。

英文摘要

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.