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抑制cGAS-STING通路可减轻顺铂诱导的内耳毛细胞损伤。

Inhibition of the cGAS‑STING Pathway Reduces Cisplatin-Induced Inner Ear Hair Cell Damage.

作者信息

Sun Ying, Zou Shengyu, Xu Xiaoxiang, Xu Shan, Sun Haiying, Tang Mingliang, Kong Weijia, Chen Xiong, He Zuhong

机构信息

Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.

Department of Otolaryngology, The First Hospital of China Medical University, Shenyang, 110001, China.

出版信息

Neurosci Bull. 2025 Mar;41(3):359-373. doi: 10.1007/s12264-024-01334-8. Epub 2024 Dec 16.

DOI:10.1007/s12264-024-01334-8
PMID:39676140
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11876498/
Abstract

Although cisplatin is a widely used chemotherapeutic agent, it is severely toxic and causes irreversible hearing loss, restricting its application in clinical settings. This study aimed to determine the molecular mechanism underlying cisplatin-induced ototoxicity. Here, we established in vitro and in vivo ototoxicity models of cisplatin-induced hair cell loss, and our results showed that reducing STING levels decreased inflammatory factor expression and hair cell death. In addition, we found that cisplatin-induced mitochondrial dysfunction was accompanied by cytosolic DNA, which may act as a critical linker between the cyclic GMP-AMP synthesis-stimulator of interferon genes (cGAS-STING) pathway and the pathogenesis of cisplatin-induced hearing loss. H-151, a specific inhibitor of STING, reduced hair cell damage and ameliorated the hearing loss caused by cisplatin in vivo. This study underscores the role of cGAS-STING in cisplatin ototoxicity and presents H-151 as a promising therapeutic for hearing loss.

摘要

尽管顺铂是一种广泛使用的化疗药物，但它具有严重的毒性，会导致不可逆的听力损失，限制了其在临床环境中的应用。本研究旨在确定顺铂诱导耳毒性的分子机制。在此，我们建立了顺铂诱导毛细胞损失的体外和体内耳毒性模型，我们的结果表明，降低STING水平可减少炎症因子表达和毛细胞死亡。此外，我们发现顺铂诱导的线粒体功能障碍伴随着胞质DNA，这可能是环磷酸鸟苷-腺苷合成酶-干扰素基因刺激物（cGAS-STING）途径与顺铂诱导的听力损失发病机制之间的关键联系。STING的特异性抑制剂H-151减少了毛细胞损伤，并改善了顺铂在体内引起的听力损失。本研究强调了cGAS-STING在顺铂耳毒性中的作用，并提出H-151作为一种有前景的听力损失治疗药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/981b/11876498/a850703c8b45/12264_2024_1334_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/981b/11876498/5eb237b0cfa7/12264_2024_1334_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/981b/11876498/58b72e45af6c/12264_2024_1334_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/981b/11876498/09fc04130088/12264_2024_1334_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/981b/11876498/10cc8044da2d/12264_2024_1334_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/981b/11876498/dadc3d289713/12264_2024_1334_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/981b/11876498/a850703c8b45/12264_2024_1334_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/981b/11876498/5eb237b0cfa7/12264_2024_1334_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/981b/11876498/58b72e45af6c/12264_2024_1334_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/981b/11876498/09fc04130088/12264_2024_1334_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/981b/11876498/10cc8044da2d/12264_2024_1334_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/981b/11876498/dadc3d289713/12264_2024_1334_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/981b/11876498/a850703c8b45/12264_2024_1334_Fig6_HTML.jpg

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