Atovaquone-induced therapeutic rewiring of melanoma metabolism

Melanoma continues to be the deadliest form of skin cancer, emphasizing the need for new therapeutic strategies. Targeting tumor metabolism, particularly oxidative phosphorylation (OXPHOS) has emerged as a promising approach due its role in melanoma tumor survival, metastasis, and treatment resistance. In this study, we investigate the metabolic and antitumor effects of atovaquone, an FDA-approved and safe OXPHOS inhibitor that has not been previously tested in melanoma. We show that atovaquone rapidly and effectively inhibits OXPHOS and impairs glycolysis in melanoma, leading to metabolic reprogramming observed via metabolic imaging and marked depletion in energy (ATP) stores. Atovaquone also induces oxidative stress, evidenced by increased reactive oxygen species levels, DNA damage, and upregulation of antioxidant proteins. Moreover, atovaquone reduced melanoma cell viability and migration in vitro, and slowed tumor growth in vivo. Notably, these effects were observed in both BRAF-wild-type and mutant melanoma models, suggesting its potential as an effective treatment across different subtypes. Our study identifies atovaquone as a metabolic disruptor with antitumor activity against melanoma, supporting further investigation as a repurposed therapeutic strategy.