Ferroptosis, characterized by iron‐dependent lipid reactive oxygen species (ROS) accumulation, plays a pivotal role in cisplatin‐induced ototoxicity. Existing research has suggested that in cisplatin‐mediated damage to auditory cells and hearing loss, ferroptosis is partially implicated. 4‐Octyl itaconate (4‐OI), derived from itaconic acid, effectively permeates cell membranes, showcasing potent anti‐inflammatory as well as antioxidant effects in several disease models. Our study aimed to investigate the effect of 4‐OI on cisplatin‐induced ferroptosis and the underlying molecular mechanisms. The survival rates of HEI‐OC1 cells and mice cochlea hair cells were measured by CCK8 and immunofluorescence, respectively. The auditory brainstem response (ABR) audiometry was used to detect changes in hearing thresholds in mice before and after treatment. Levels of ROS were evaluated by DCFH‐DA. Real‐time PCR quantified inflammatory cytokines TNF‐α, IL‐6 and IL‐1β. Network Pharmacology and RNA sequencing (RNA‐seq) analysis of the potential mechanism of 4‐OI resistance to cisplatin‐induced ferroptosis. The expressions of ferroptosis‐related factors (GPX4, SLC7A11 and PTGS2) and important antioxidant factors (NRF2, HO‐1, GCLC and NQO1) were tested by real‐time PCR, Western blot and immunofluorescence. Results demonstrated cisplatin‐induced significant ROS and inflammatory factor release, reduced NRF2 expression, hindered nuclear translocation and activated ferroptosis. Pretreatment with 4‐OI exhibited anti‐inflammatory and antioxidant effects, along with resistance to ferroptosis, ultimately mitigating cisplatin‐induced cell loss. In the present study, we show that 4‐OI inhibits cisplatin‐induced ferroptosis possibly through activation of the NRF2/HO‐1 signalling pathway, thereby exerting a protective effect against cisplatin‐induced damage to auditory cells, and providing a new therapeutic strategy for cisplatin‐induced hearing loss.

中文翻译：

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衣康酸 4-辛酯可能通过激活 NRF2/HO-1 信号通路减轻顺铂诱导的铁死亡

铁死亡以铁依赖性脂质活性氧（ROS）积累为特征，在顺铂诱导的耳毒性中发挥着关键作用。现有研究表明，顺铂介导的听觉细胞损伤和听力损失与铁死亡有关。衣康酸 4-辛酯 (4-OI) 源自衣康酸，可有效渗透细胞膜，在多种疾病模型中显示出有效的抗炎和抗氧化作用。我们的研究旨在探讨 4-OI 对顺铂诱导的铁死亡的影响及其潜在的分子机制。分别通过CCK8和免疫荧光测量HEI-OC1细胞和小鼠耳蜗毛细胞的存活率。使用听觉脑干反应（ABR）测听法来检测小鼠治疗前后听力阈值的变化。通过 DCFH-DA 评估 ROS 水平。实时 PCR 定量炎症细胞因子 TNF-α、IL-6 和 IL-1β。网络药理学和 RNA 测序 (RNA-seq) 分析 4-OI 抵抗顺铂诱导的铁死亡的潜在机制。通过实时PCR、Western blot和免疫荧光检测铁死亡相关因子（GPX4、SLC7A11和PTGS2）和重要抗氧化因子（NRF2、HO-1、GCLC和NQO1）的表达。结果表明，顺铂诱导显着的 ROS 和炎症因子释放，降低 NRF2 表达，阻碍核转位并激活铁死亡。 4-OI 预处理表现出抗炎和抗氧化作用，以及对铁死亡的抵抗力，最终减轻顺铂诱导的细胞损失。在本研究中，我们发现4-OI可能通过激活NRF2/HO-1信号通路来抑制顺铂诱导的铁死亡，从而对顺铂诱导的听觉细胞损伤发挥保护作用，为顺铂诱导的听觉细胞损伤提供新的治疗策略。顺铂引起的听力损失。