2. Academic Validation
  3. Cisplatin transported by COX17 induces cochlear damage by binding Myosin IIA to regulate cell pyroptosis induced by mitochondrial dysfunction

Cisplatin transported by COX17 induces cochlear damage by binding Myosin IIA to regulate cell pyroptosis induced by mitochondrial dysfunction

  • Life Sci. 2025 Nov 1:380:123961. doi: 10.1016/j.lfs.2025.123961.
Jiahui Peng 1,  Guofang Tao 1,  Xubo Chen 1,  Yufeng Ai 1,  Ruosha Lai 2,  Wei Liu 2,  Bing Hu 3,  Yingying Xu 1,  Bingbin Xie 1,  Lihua Li 4
Affiliations

Affiliations

  • 1 Department of Otolaryngology Head and Neck Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
  • 2 Department of Otolaryngology, Head and Neck Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
  • 3 Department of Otolaryngology Head and Neck Surgery, the Second People' s Hospital of Shenzhen, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, Guangdong, China.
  • 4 Department of Otolaryngology Head and Neck Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China. Electronic address: ndefy12392@ncu.edu.cn.
PMID: 40945651 DOI: 10.1016/j.lfs.2025.123961
Abstract

Aims: Cytochrome c oxidase copper chaperone 17 (COX17) could transport cisplatin to Cancer cell mitochondria. Whether COX17 transports cisplatin to cochlear mitochondria and induces Pyroptosis to participate in cisplatin-induced ototoxicity remains unknown.

Materials and methods: A cisplatin-induced hearing loss model was constructed in rats, and the role of COX17 and Myosin IIA in cisplatin-induced hearing loss and cochlear injury was evaluated by auditory brainstem response test and H&E staining. Cisplatin binding to Myosin IIA was verified through cisplatin agar-pull-down assays and drug affinity responsiveness target stability. The interaction between Myosin IIA and F-actin was verified using co-immunoprecipitation. Various techniques were used to study how cisplatin causes damage to cochlear hair cells and induces Pyroptosis, including immunofluorescence staining, and flow cytometry.

Key findings: Our findings indicated that downregulating COX17 inhibits cisplatin accumulation in mitochondria, leading to improved cell survival, and inhibits pyrodeath. Upon entering the mitochondria, cisplatin transported by COX17 binds to Myosin IIA, enhancing its expression and subsequently promoting the expression of F-actin and p-DRP1 while inhibiting the expression of Mfn1, Mfn2, and OPA1. Furthermore, the interaction between Myosin IIA and F-actin was determined. Downregulation of Myosin IIA or treatment with mitochondrial fission inhibitors resulted in reduced mitochondrial ROS release and increased Pyroptosis. In vivo studies demonstrated that downregulating COX17 or Myosin IIA improved cisplatin-induced hearing loss and cochlear damage in rats.

Significance: These findings offer new insights and potential targets for the preventing and treatment of cisplatin-induced ototoxicity.

Keywords

COX17; Cisplatin ototoxicity; Myosin IIA; mitochondrial damage; pyroptosis.

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