鞘脂代谢失调通过线粒体功能障碍和内在凋亡驱动顺铂诱导的耳毒性
Sphingolipid Metabolic Dysregulation Drives Cisplatin-Induced Ototoxicity Through Mitochondrial Dysfunction and Intrinsic Apoptosis.
文献信息
| PMID | 42977102 |
|---|---|
| 原文 | 在 PubMed 查看原文 ↗ |
| 发表日期 | 2026 |
| 作者 | Xian Gao |
| 作者单位 | ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, Fudan University, Shanghai 200031, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China. |
| 期刊 | Free radical biology & medicine |
| SCI 分区 | Q1 |
| IF | 8.8 |
| 研究类型 | 基础研究 · 基础／转化 |
| 所属专科 | 耳科 |
中文摘要
顺铂是一种广泛使用的化疗药物，但其临床应用受到不可逆性感音神经性听力损失的限制。鞘脂代谢日益被认为与感觉毛细胞（HC）存活有关，但其在顺铂诱导的耳毒性中的作用仍不清楚。在此，我们研究了鞘脂失调在顺铂耳毒性中的参与，并评估了芬戈莫德（FTY720）——一种FDA批准的鞘氨醇-1-磷酸（S1P）受体调节剂——的耳保护作用及机制。多种S1P通路调节剂在体外保护耳蜗HC免受顺铂诱导的损伤，支持S1P信号通路的参与。FTY720在急性和慢性顺铂诱导听力损失小鼠模型中保留了听觉功能，并减少了HC、带状突触和螺旋神经节神经元的丢失。多组学和分子分析显示，FTY720恢复了顺铂诱导的鞘脂代谢失调并激活了PI3K/AKT信号通路。因此，FTY720减轻了线粒体功能障碍和线粒体依赖的内在凋亡。重要的是，FTY720并未减弱顺铂诱导的细胞毒性，也未抑制其在癌细胞中的抗增殖作用，这通过活力检测、Calcein AM/碘化丙啶（PI）双染和Ki67分析得到证实。总之，这些发现揭示了顺铂诱导耳毒性中的鞘脂代谢-PI3K/AKT-线粒体凋亡轴，并支持FTY720作为一种潜在的耳保护策略，且不损害顺铂介导的肿瘤细胞杀伤作用。
英文摘要
Cisplatin is a widely used chemotherapeutic agent, but its clinical application is limited by irreversible sensorineural hearing loss. Sphingolipid metabolism is increasingly implicated in sensory hair cell (HC) survival, yet its role in cisplatin-induced ototoxicity remains unclear. Here, we investigated the involvement of sphingolipid dysregulation in cisplatin ototoxicity and evaluated the otoprotective effects and mechanisms of fingolimod (FTY720), an FDA-approved sphingosine-1-phosphate (S1P) receptor modulator. Multiple S1P pathway modulators protected cochlear HCs from cisplatin-induced injury in vitro, supporting the involvement of S1P signaling. FTY720 preserved auditory function and reduced HC, ribbon synapse, and spiral ganglion neuron loss in acute and chronic mouse models of cisplatin-induced hearing loss. Multi-omics and molecular analyses revealed that FTY720 restored cisplatin-induced sphingolipid metabolic dysregulation and activated PI3K/AKT signaling. FTY720 consequently alleviated mitochondrial dysfunction and mitochondria-dependent intrinsic apoptosis. Importantly, FTY720 did not attenuate cisplatin-induced cytotoxicity or suppress its antiproliferative effects in cancer cells, as confirmed by viability, Calcein AM/propidium iodide (PI) double staining, and Ki67 analysis. Collectively, these findings reveal a sphingolipid metabolism-PI3K/AKT-mitochondrial apoptosis axis in cisplatin-induced ototoxicity and support FTY720 as a potential otoprotective strategy without compromising cisplatin-mediated tumor cell killing.