A proteomic study analyzing 151 tumor and normal samples has uncovered that aggressive melanomas exhibit hyperactivation of mitochondrial protein synthesis and metabolic pathways fueling tumor growth. This "mitochondrial-protein signature" correlates strongly with melanoma severity. Intriguingly, certain antibiotics originally designed as bacterial protein synthesis inhibitors effectively disrupt melanoma mitochondrial function, selectively impeding tumor cell survival. These findings open therapeutic avenues targeting melanoma’s energy production machinery with repurposed drugs, potentially advancing precision oncology.