Abstract

Mitochondrial metabolic reprogramming is a reason for the cisplatin‐resistant state of head and neck squamous cell carcinoma (HNSCC) and confers cisplatin resistance. The functions of cytochrome c oxidase subunit 5a (COX5A) and its target interferon‐stimulated gene 15 (ISG15) in modulating cellular processes, cisplatin resistance, and mitochondrial impairment in HNSCC were studied in this paper. FaDu and FaDu‐DDP cell lines were cultured and then transfected to achieve COX5A/ISG15 knockdown or COX5A overexpression. Zebrafish xenograft models were employed to validate in vivo. Quantitative real‐time PCR and Western blot were used to assess the expression of COX5A and ISG15. Cell viability, migration, and apoptosis were investigated using CCK‐8, Transwell/Wound healing, and flow cytometry assays. Mitochondrial activities were evaluated based on mitochondrial mass, ATP production efficiency, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS). Our results showed that the expression of COX5A increased in FaDu‐DDP cells. Silencing COX5A suppressed cell viability and migration, induced apoptosis, increased cisplatin sensitivity, and overexpression of COX5A had the opposite effects. COX5A silencing led to mitochondrial dysfunction, including reduced mitochondrial mass, ATP deficiency, decreased MMP, and increased ROS. ISG15 was identified as a downstream molecule negatively regulated by COX5A. ISG15 modulation partially reversed the effects of COX5A on cellular behaviors, cisplatin resistance, and mitochondrial dysfunction. COX5A promotes cell growth and enhances cisplatin resistance in HNSCC. These effects are mediated through the regulation of mitochondrial function via the downstream effector ISG15. Thus, our findings demonstrated that COX5A‐mediated mitochondrial bioenergetics are suitable targets for enhancing the cisplatin sensitivity of HNSCC.