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

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

doi:10.1007/s12264-024-01334-8

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

Neurosci Bull. 2024 Dec 16. doi: 10.1007/s12264-024-01334-8. Online ahead of print.

Authors

Ying Sun¹, Shengyu Zou¹, Xiaoxiang Xu¹, Shan Xu², Haiying Sun³, Mingliang Tang⁴, Weijia Kong³, Xiong Chen⁵, Zuhong He^{6

7}

Affiliations

¹ Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
² Department of Otolaryngology, The First Hospital of China Medical University, Shenyang, 110001, China.
³ Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
⁴ Institute for Cardiovascular Science and Department of Cardiovascular Surgery of the First Affiliated Hospital, Suzhou Medical College of Soochow University, Soochow University, Suzhou, 215000, China.
⁵ Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China. [email protected].
⁶ Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China. [email protected].
⁷ State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China. [email protected].

PMID: 39676140
DOI: 10.1007/s12264-024-01334-8

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.

Keywords: Hair cell; Hearing loss; Mitochondrial dysfunction; Ototoxicity; cGAS-STING.