Inhibition of the cGAS‑STING Pathway Reduces Cisplatin-Induced Inner Ear Hair Cell Damage
Ying Sun1 · Shengyu Zou1 · Xiaoxiang Xu1 · Shan Xu3 · Haiying Sun4 · Mingliang Tang5 · Weijia Kong4 · Xiong Chen1 · Zuhong He1,21 Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
2 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
3 Department of Otolaryngology, The First Hospital of China Medical University, Shenyang 110001, China
4 Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
5 Institute for Cardiovascular Science and Department of Cardiovascular Surgery of the First Afliated Hospital, Suzhou Medical College of Soochow University, Soochow University, Suzhou 215000, China
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
Ototoxicity; Hearing loss; cGAS-STING; Hair cell; Mitochondrial dysfunction
