FAK Dependent Focal Adhesion Remodeling Drives Arsenical Vesicant Induced Skin Injury

Abstract

Chemical vesicants cause severe skin injury characterized by inflammation, tissue destruction, and separation of the epidermis from the underlying dermis. However, the molecular mechanisms linking vesicant exposure to the disruption of epidermal adhesion remain poorly understood. Phenylarsine oxide (PAO), a commonly used lewisite analog, is a potent inducer of cutaneous blistering and a strong inhibitor of protein tyrosine phosphatases. Here, we show that PAO rapidly induces focal adhesion kinase (FAK) phosphorylation and downstream signaling in epidermal keratinocytes, accompanied by accelerated focal adhesion disassembly and molecular turnover. Genetic ablation of FAK stabilizes focal adhesions and markedly suppresses PAO-induced adhesion remodeling. Importantly, epidermal-specific deletion of FAK protects mouse skin from PAO-induced microvesication, inflammatory responses, and cell death. Pharmacological inhibition of FAK similarly preserves focal adhesion stability in vitro and attenuates PAO-induced skin injury in vivo, phenocopying the protective effects of genetic FAK deficiency. Together, our findings identify aberrant FAK activation as a critical signaling event linking arsenical vesicant exposure to focal adhesion failure and skin vesication, and suggest that targeting FAK may provide a therapeutic strategy to mitigate chemical vesicant-induced skin injury.