Red human hair pheomelanin is a potent pro-oxidant mediating UV-independent contributory mechanisms of melanomagenesis

The highest incidence of melanoma in red haired individuals is attributed to the synthesis and phototoxic properties of pheomelanin pigments. Recently, pheomelanin has also been implicated in UV-independent pathways of oxidative stress; however, the underlying mechanisms have remained uncharted. Herein, we disclose the unprecedented property of purified red human hair pheomelanin (RHP) to promote (i) the oxygen-dependent depletion of major cell antioxidants, for example glutathione and NADH; (ii) the autoxidative formation of melanin pigments from their precursors. RHP would thus behave as a unique living' polymer and biocatalyst that may grow by simple exposure to monomer building blocks and may trigger autoxidative processes. These results yield new clues as to the origin of the pro-oxidant state in the red hair phenotype, uncover non-enzymatic pathways of melanogenesis, and pave the way to innovative strategies for melanoma prevention.