Malignant melanoma causes the majority of skin cancer-related deaths in the United States representing a public health burden of considerable magnitude. Our recent research has identified artemisinins, an important class of redox-antimalarials in clinical use worldwide, as redox-directed anticancer agents that target disruption of cellular iron homeostasis, a common alteration of premalignant and malignant cells that causes hypersensitivity to cytotoxic oxidative stress. In this R01 application entitled 'Repurposing Clinical ACT Antimalarials for Experimental Melanoma Intervention', we test the hypothesis that oncogene-driven dysregulation of iron homeostasis represents a molecular Achilles heel characteristic of melanomagenesis that can be targeted by artemisinin-endoperoxide antimalarials. In this comprehensive project, we also test feasibility of using artemisinin-based combination therapeutics (ACT), FDA-approved for pharmacotherapeutic anti-malaria intervention, targeting malignant melanoma in relevant disease models: aim #1: First, the mechanistic relationship between dysregulated c- MYC and transferrin receptor expression, iron homeostasis, and cellular hypersensitivity to artemisinin-based redox intervention will be examined in cell culture and human premalignant and tumor tissue interrogated in microarray format. Novel molecular targets modulated through covalent adduction after iron-dependent artemisinin activation will be identified based on proteomic experimentation using a fluorescently labeled artemisinin probe followed by in vivo efficacy testing in a spontaneous murine genetic melanoma model. aim #2: Following our prior studies on antimelanoma activity of the autophagy-directed ACT antimalarial amodiaquine, we explore mechanism and feasibility of amodiaquine-based experimental chemotherapeutic intervention targeting early and late melanomagenesis. aim #3:Finally, we will test the hypothesis that artemisinin-based intervention combined with specific autophagy-directed ACT antimalarials (amodiaquine, piperaquine, lumefantrine) provides improved therapeutic efficacy inhibiting tumor growth and overcoming BRAF-inhibitor resistance in preclinical xenograft models. The proposed research guides the rational design of future preclinical/clinical studies that promise to facilitate repurposing of FDA-approved ACT- antimalarials for anti-melanoma intervention, benefitting patients in the very near future.