GSDMD-mediated mitochondrial dysfunction in marginal cells: A potential driver of inflammation and stria vascularis damage in CIHL
Data files
Mar 10, 2025 version files 3.67 MB
-
All_GeneDiffExp.xls
3.66 MB
-
README.md
4.34 KB
Abstract
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, leading to abnormal mitochondrial aggregation and oxidative stress. The consequent mitochondrial dysfunction in MCs might result in the severe progression of inflammation, SV damage, and HC loss. Notably, the pharmacological inhibition of pyroptosis using the FDA-approved drug disulfiram effectively alleviated the symptoms of CIHL. Collectively, these findings offer a broad avenue for inhibiting pyroptosis-induced cisplatin ototoxicity and provide valuable theoretical insights for the clinical management of CIHL.
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 libraries were prepared and quantified using the Agilent 2100 Bioanalyzer and ABI StepOnePlus Real-Time PCR System and sequenced on the Illumina sequencing platform. Raw data obtained from sequencing were filtered, and the clean reads obtained were aligned to the reference genome. Differentially expressed genes (DEGs) were identified using the DESeq2 package with a threshold of |log2 fold change| > 1 and an adjusted p-value < 0.05.
Files and variables
File: All_GeneDiffExp.xls
Description: The data is the 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). In this table, "WT" refers to WT, "WT_with_Cis" refers to WT+cisplatin, "KO" refers to Gsdmd−/−, "KO_with_Cis" refers to Gsdmd−/−+cisplatin. In the document, each variable (column name) and the corresponding explanation are shown below:
(1) GeneID: The gene Entrez ID
(2) log2FoldChange(KO-VS-KO_with_Cis.DEseq2): log2-transformed fold change in gene expression between KO and KO_with_Cis .
(3) Padj(KO-VS-KO_with_Cis.DEseq2): Adjusted p-value of the fold change (KO vs. KO_with_Cis).
(4) Up/Down-Regulation(KO_with_Cis/KO): Direction of regulation: "Up" if expression is higher in KO_with_Cis vs. KO, "Down" if lower.
(5) log2FoldChange(WT-VS-KO.DEseq2): log2-transformed fold change in gene expression between WT and KO .
(6) Padj(WT-VS-KO.DEseq2): Adjusted p-value of the fold change (WT vs. KO).
(7) Up/Down-Regulation(KO/WT): Direction of regulation: "Up" if expression is higher in KO vs. WT, "Down" if lower.
(8) log2FoldChange(WT-VS-KO_with_Cis.DEseq2): log2-transformed fold change in gene expression between WT and KO_with_Cis.
(9) Padj(WT-VS-KO_with_Cis.DEseq2): Adjusted p-value of the fold change (WT vs. KO_with_Cis)
(10) Up/Down-Regulation(KO_with_Cis/WT): Direction of regulation: "Up" if expression is higher in KO_with_Cis vs. WT, "Down" if lower.
(11) log2FoldChange(WT-VS-WT_with_Cis.DEseq2): log2-transformed fold change in gene expression between WT and WT_with_Cis.
(12) Padj(WT-VS-WT_with_Cis.DEseq2): Adjusted p-value of the fold change (WT vs. WT_with_Cis)
(13) Up/Down-Regulation(WT_with_Cis/WT): Direction of regulation: "Up" if expression is higher in WT_with_Cis vs. WT, "Down" if lower.
(14) log2FoldChange(WT_with_Cis-VS-KO_with_Cis.DEseq2): log2-transformed fold change in gene expression between WT_with_Cis and KO_with_Cis.
(15) Padj(WT_with_Cis-VS-KO_with_Cis.DEseq2): Adjusted p-value of the fold change (WT_with_Cis vs. KO_with_Cis)
(16) Up/Down-Regulation(KO_with_Cis/WT_with_Cis): Direction of regulation: "Up" if expression is higher in KO_with_Cis vs. WT_with_Cis, "Down" if lower.
(17) Symbol: Gene symbol
(18) Description: Functional description of the gene.
(19) GeneType: Classification of the gene type.
Additionally, cells marked with * indicate: Non-significant results (Padj > 0.05), low-count genes excluded by DESeq2, or data filtered during quality control.
Variables
The dataset includes two variables: (1) cisplatin treatment (with or without cisplatin) and (2) Gsdmd gene status (wild-type or knockout).