GSDMD-mediated mitochondrial dysfunction in marginal cells: A potential driver of inflammation and stria vascularis damage in CIHL

Inflammation is among the known causes of cisplatin-induced hearing loss (CIHL), but its exact pathophysiological mechanisms remain unclear. Herein, we demonstrated that pyroptosis—a recently identified inflammatory type of regulated cell death dependent on gasdermin D (GSDMD)—was activated in the cochleae of cisplatin-treated mice, causing CIHL. Meanwhile, treatment with the GSDMD inhibitor necrosulfonamide alleviated CIHL in these mice. To further examine the role of GSDMD-mediated pyroptosis in CIHL, we conducted experiments in Gsdmd-deficient mice. Gsdmd−/− mice demonstrated significantly lower cisplatin-induced cochlear damage than control mice and appeared to be invulnerable to CIHL. Furthermore, GSDMD-mediated pyroptosis in the stria vascularis (SV), but not in the hair cells (HCs), played a dominant role in CIHL. In marginal cells (MCs) of SV, cisplatin induced caspase-dependent GSDMD cleavage, and the pore-forming N-terminal of GSDMD rapidly localized to the mitochondria, ..., , , # GSDMD-mediated mitochondrial dysfunction in marginal cells: A potential driver of inflammation and stria vascularis damage in CIHL

[https://doi.org/10.5061/dryad.b2rbnzsrj ](https://doi.org/10.5061/dryad.b2rbnzsrj)

## Description of the data and file structure

 To investigate the role of GSDMD in cisplatin-induced ototoxicity, we performed transcriptomic analysis on the cochleae of four experimental groups: (1) wild-type (WT) mice, (2) WT mice treated with cisplatin (WT+cisplatin), (3) *Gsdmd *knockout mice (*Gsdmd−/−*), and (4) *Gsdmd−/−* mice treated with cisplatin (*Gsdmd−/−*+cisplatin). Total RNA was extracted from bilateral cochleae (3 mice per group) using the TRIzol reagent (Vazyme, R411-01). The extracted RNA was sent to Igenecode Gene Technology Corporation (Beijing) for library establishment and sequencing analysis. Briefly, the constructed librarie...,

炎症是顺铂诱导性听力损失（cisplatin-induced hearing loss, CIHL）的已知病因之一，但其确切病理生理机制仍不明确。本文中，我们证实细胞焦亡（pyroptosis）——一种近年发现的、依赖于Gasdermin D（GSDMD）的炎症性调控细胞死亡类型——在顺铂处理小鼠的耳蜗中被激活，导致CIHL。同时，使用GSDMD抑制剂坏死磺酰胺（necrosulfonamide）处理可缓解这些小鼠的CIHL。为进一步探究GSDMD介导的细胞焦亡在CIHL中的作用，我们在Gsdmd缺陷小鼠（Gsdmd-deficient mice）中开展实验。Gsdmd−/−小鼠的顺铂诱导耳蜗损伤显著低于对照组小鼠，且似乎对CIHL具有抗性。此外，血管纹（stria vascularis, SV）中GSDMD介导的细胞焦亡（而非毛细胞（hair cells, HCs）中的）在CIHL中发挥主导作用。在SV的边缘细胞（marginal cells, MCs）中，顺铂诱导半胱天冬酶（caspase）依赖的GSDMD切割，且GSDMD的成孔N端快速定位于线粒体，……，# GSDMD介导的边缘细胞线粒体功能障碍：CIHL中炎症与血管纹损伤的潜在驱动因素
[https://doi.org/10.5061/dryad.b2rbnzsrj](https://doi.org/10.5061/dryad.b2rbnzsrj)

## 数据与文件结构描述

为探究GSDMD在顺铂耳毒性中的作用，我们对四组实验小鼠的耳蜗进行转录组分析：（1）野生型（wild-type, WT）小鼠；（2）顺铂处理的WT小鼠（WT+cisplatin）；（3）Gsdmd基因敲除小鼠（Gsdmd−/−）；（4）顺铂处理的Gsdmd−/−小鼠（Gsdmd−/−+cisplatin）。使用TRIzol试剂（Vazyme公司，货号R411-01）从双侧耳蜗（每组3只小鼠）中提取总RNA。提取的RNA被送往北京Igenecode基因科技有限公司进行文库构建和测序分析。简言之，构建的文库……