Octenidine Dihydrochloride Suppresses Nasopharyngeal Carcinoma Growth through Inducing Mitochondrial Respiratory Dysfunction

Abstract Nasopharyngeal carcinoma (NPC) remains a clinically challenging malignancy, and additional mechanistically defined therapeutic strategies with acceptable toxicity profiles are needed. In this study, we evaluated the antitumor efficacy of octenidine dihydrochloride (OCT) as a repurposed therapeutic agent for NPC. OCT significantly suppressed the proliferation of HK-1 and SUNE-1 cells and induced apoptosis in a concentration-dependent manner. Intragastric administration of OCT attenuated tumor growth in a subcutaneous xenograft model without detectable systemic toxicity. To uncover the underlying mechanism of its antitumor activity, we performed data-independent acquisition (DIA)-based quantitative proteomics to profile the protein alterations in OCT-treated NPC cells and found that OCT treatment preferentially downregulated mitochondrial complex I-associated oxidative phosphorylation proteins, indicating coordinated remodeling of the mitochondrial respiratory proteome. Consistent with these proteomic findings, Seahorse XF metabolic flux analysis demonstrated impaired mitochondrial respiration after OCT treatment, including reduced oxygen consumption and respiratory capacity. Functionally, aspartate supplementation partially rescued OCT-induced growth inhibition, supporting a mechanistic link between mitochondrial respiratory dysfunction and the OCT-mediated anti-NPC effects. Collectively, our findings demonstrate that OCT suppresses NPC growth by perturbing mitochondrial oxidative phosphorylation, providing a mechanistic rationale for further investigation of OCT in the treatment of NPC.