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 <i>Gsdmd-</i>deficient mice<i>. Gsdmd<sup>-/-</sup></i> 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.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-03-11
DOI
https://doi.org/10.1073/pnas.2415805122
Citations
8
Primary Topic
Hearing, Cochlea, Tinnitus, Genetics
Type
article
Field-Weighted Citation Impact
11.72

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article

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

Xiuli Bi, Siwei Guo, Xiaoxu Zhao, Wen Li et al.
8 citations
Proceedings of the National Academy of Sciences
Hearing, Cochlea, Tinnitus, Genetics
11.72
article

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

Xiuli Bi, Siwei Guo, Xiaoxu Zhao, Wen Li, Shengda Cao, Liya Zhu, Guodong Hong, Ruifeng Qiao, Ziyi Liu, Ying Liu, Xiaohan Zhang, Wei Yuan, Miao Chang, Renjie Chai, Jing Zhang, Jiangang Gao, Xiaolong Fu, Ming Xia, Fengyue Dong, Yu Xiao
article en
8 citations

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 <i>Gsdmd-</i>deficient mice<i>. Gsdmd<sup>-/-</sup></i> 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.

Proceedings of the National Academy of SciencesVol. 122(11)
Beijing Institute of Technology (CN), University of Electronic Science and Technology of China (CN), Shandong University (CN), Nantong University (CN), Southeast University (BD), Zhongda Hospital Southeast University (CN), Aerospace Center Hospital (CN), Shandong Provincial Hospital (CN), Qilu Hospital of Shandong University (CN), First People's Hospital of Chongqing (CN), Shandong First Medical University (CN), State Key Laboratory of Digital Medical Engineering (CN), Southeast University (CN)
National Natural Science Foundation of China, Natural Science Foundation of Shandong Province
Good health and well-being
Openalex Percentile: Top 1%
Hearing, Cochlea, Tinnitus, Genetics
11.72
DOIOpen Access PDFOpenAlex
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