Polyamine Metabolism and the DHPS/eIF5A Hypusination Axis: From Metabolic Reprogramming to a Therapeutic Achilles’ Heel in Melanoma

The polyamine metabolic pathway, an evolutionarily conserved nexus integrating nutrient sensing, translation control, and cellular proliferation, is fundamentally rewired in cancer. Melanoma, a malignancy of melanocytes notorious for its metastatic propensity and therapy resistance, exhibits a profound dependency on this pathway, extending beyond mere polyamine abundance to the specialized function of their derivative, hypusine. This review synthesizes cutting-edge insights into the deoxyhypusine synthase (DHPS)/eukaryotic initiation factor 5A (eIF5A) hypusination circuit as a critical amplifier of oncogenic signaling in melanoma. We dissect its role as a translational rheostat for pro-tumorigenic proteomes, a driver of phenotypic plasticity underpinning invasion and vasculogenic mimicry, and a modulator of the immunosuppressive tumor microenvironment. Moving beyond the classical inhibitor GC7, we explore the emergence of novel allosteric DHPS inhibitors with compelling preclinical efficacy. Finally, we propose a paradigm shift: targeting the DHPS/eIF5A axis represents a strategy to disrupt the “non-oncogene addiction” of melanoma—its reliance on hyperactive translation and adaptive survival mechanisms—offering a promising avenue alongside targeted therapies and immunotherapies.