PROJECT SUMMARYNonmelanoma skin cancer (NMSC) is the most common malignancy in the United States representing aconsiderable public health burden. Pharmacological suppression of skin photocarcinogenesis has shownpromise in preclinical and clinical studies but more efficacious photochemopreventive agents are needed.Here we test feasibility of harnessing pharmacological disruption of intracellular zinc homeostasis forphotochemoprevention in vitro and in vivo. Employing the zinc ionophore and FDA-approved microbicidalagent zinc pyrithione (ZnPT) used worldwide in over-the-counter (OTC) topical consumer products we will first(aim #1) explore tissue factors determining zinc-senistivity that may explain the exquisite vulnerability ofmalignant keratinocytes towards zinc ion overload. To this end molecular determinants underlying altered zincion homeostasis in SCC will be examined (ZIP2 (SLC39A2) and ZnT6 (SLC30A6)). In aim #2 we will compare'preventive' and 'interventional' efficacy of topical ZnPT in the SKH-1 murine photocarcinogenesis modelsubstantiating feasibility of repurposing a safe readily available topical OTC drug for zinc-directedphotochemoprevention of solar UV-induced NMSC.