Arsenicals such as lewisite, diethylchloroarsine, diphenylchlorarsine, and diphenylcyanoarsine are extremely toxic chemicals that have been used in chemical warfare since World War I and continue to remain a threat to humans, who may be exposed through accidental or intentional mass population exposure. Topical exposure to these agents results in severe cutaneous blistering, inflammation and pain, and therapeutic strategies that safely and effectively attenuate this damage remain urgently needed. Such a strategy has long remained elusive in large part because the molecular mechanisms that underlie the cutaneous damage caused by arsenicals had not been identified. With our previous award, we developed murine and porcine models that, upon topical arsenical exposure, develop cutaneous lesions nearly identical to those that occur in humans. Employing these animal models, we identified a master regulatory signaling cascade underpinning the complex pathobiology of arsenicals. Mechanistically, the inflammatory responses, cell death, tissue disruption, and pain pathways induced by cutaneous arsenicals exposure are mediated by the induction of endoplasmic reticulum (ER) stress and reactive oxygen species generation and subsequent activation of unfolded protein response (UPR) signaling, particularly that involving the ATF4-eIF2α axis. Phosphorylated eIF2α, which we found to be upregulated after arsenicals exposure, blocks translation of most nascent proteins but upregulates the translation of the ATF4 transcription factor. RNA-Seq and CHIP-Seq data confirmed an unbiased role of ATF4 in the pathogenesis of the skin lesions and identified a unified role of ATF4-regulated proteins in this injury. Therefore, we investigated the therapeutic potential of the chemical chaperone 4-phenylbutyric acid (4-PBA), which has been shown to enhance protein folding and reduce ER stress; the antioxidant N-acetyl cysteine (NAC); and the inhibitor of eIF2α phosphorylation ISRIB. Each of these drugs was highly effective in restoring protein translation and diminishing inflammation, tissue disruption, and pain in our mouse model. Thus, we have validated the mechanism-based efficacy of these small molecule agents against cutaneous toxicity induced by arsenicals. 4-BPA and NAC are FDA approved, thus we propose to advance these findings through the lead optimization of 4-PBA and NAC delivered by topical administration after arsenicals exposure in our murine and porcine models. Specifically, we propose to determine the efficacy of the maximum tolerated dose, the window of efficacy, and the durability of response for these drugs, alone and in combination, in treating arsenicals-mediated cutaneous injury in mice (Aim 1); to develop various topical formulations of these drugs and assess the efficacy thereof against arsenicals-mediated cutaneous injury in mice (Aim 2); and to confirm the efficacy of the identified novel outstanding formulation in our porcine model of arsenicals-mediated...