顺铂是一种常见的化疗药物，具有几乎普遍存在的耳毒性副作用。顺铂耳毒性的细胞机制尚不清楚。预防或逆转顺铂耳毒性的药物开发工作主要集中在氧化应激和细胞凋亡途径上。硫代硫酸钠是顺铂耳毒性的有效治疗方法，它与播散性肝母细胞瘤的生存率降低有关，这凸显了对更特异性药物的需求。未折叠蛋白反应（UPR）和内质网（ER）应激途径已被证明参与体内噪音引起的听力损失和耳蜗突触病的发病机制，并且这些途径广泛涉及顺铂的细胞毒性。本研究旨在确定是否可以通过 UPR 来预防顺铂耳毒性。将新生儿耳蜗培养物和 HEK 细胞暴露于顺铂和 UPR 调节药物，并测量 UPR 标记基因表达和细胞死亡。 ISRIB 是一种激活 eif2B 并下调 UPR 的促凋亡 PERK/CHOP 通路的药物，已在顺铂耳毒性的体内小鼠模型以及基于头颈鳞状细胞癌 (HNSCC) 细胞的体内测试中进行了测试。顺铂细胞毒性测定。顺铂表现出细胞死亡和凋亡的双相、非线性剂量反应，与 HEK 细胞和耳蜗培养物中 UPR 标记基因表达的不同模式相关。 ISRIB 治疗可防止顺铂引起的听力损失和毛细胞死亡，但不影响顺铂对 HNSCC 细胞活力的细胞毒性作用。这些发现表明，用 ISRIB 靶向促凋亡 PERK/CHOP 通路可以减轻顺铂的耳毒性，而不降低抗癌细胞作用，表明这可能是药物开发的可行策略。

Cisplatin is a common chemotherapy drug with a nearly universal side effect of ototoxicity. The cellular mechanisms underlying cisplatin ototoxicity are poorly understood. Efforts in drug development to prevent or reverse cisplatin ototoxicity have largely focused on pathways of oxidative stress and apoptosis. An effective treatment for cisplatin ototoxicity, sodium thiosulfate, is associated with reduced survival in disseminated hepatoblastoma, highlighting the need for more specific drugs. The unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways have been shown to be involved in the pathogenesis of noise-induced hearing loss and cochlear synaptopathy in vivo , and these pathways have been implicated broadly in cisplatin cytotoxicity. This study sought to determine whether the UPR can be targeted to prevent cisplatin ototoxicity. Neonatal cochlear cultures and HEK cells were exposed to cisplatin and UPR-modulating drugs, and UPR marker gene expression and cell death measured. Treatment with ISRIB, a drug that activates eif2B and downregulates the pro-apoptotic PERK/CHOP pathway of the UPR, was tested in an in vivo mouse model of cisplatin ototoxicity and well as a head and neck squamous cell carcinoma (HNSCC) cell-based assay of cisplatin cytotoxicity. Cisplatin exhibited a biphasic, non-linear dose-response of cell death and apoptosis that correlated with different patterns of UPR marker gene expression in HEK cells and cochlear cultures. ISRIB treatment protected against cisplatin-induced hearing loss and hair-cell death, but did not impact cisplatin's cytotoxic effects on HNSCC cell viability. These findings demonstrate that targeting the pro-apoptotic PERK/CHOP pathway with ISRIB can mitigate cisplatin ototoxicity without reducing anti-cancer cell effects, suggesting that this may be a viable strategy for drug development.