FAK Dependent Focal Adhesion Remodeling Drives Arsenical Vesicant Induced Skin Injury
- 1University of Chicago
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.
Highlights: First demonstration that focal adhesion kinase (FAK) is a critical molecular target of chemical vesicants whose dysregulation disrupts epidermal–dermal junctional integrity and initiates micro-vesicant injury.
Establishes FAK-mediated junctional disruption as an early pathogenic event that triggers and amplifies subsequent inflammatory and programmed cell-death responses following vesicant exposure.
Integrating in vivo genetic and pharmacological approaches, identifies FAK as a mechanistically validated and therapeutically actionable target for development of a mechanism-based medical countermeasure (MCM) against chemical vesicant injury.
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BibTeX
@misc{wu2026dependent,
title = {{FAK Dependent Focal Adhesion Remodeling Drives Arsenical Vesicant Induced Skin Injury}},
author = {X. Wu and H. Liu and S. Suman and A. Hoover and B. Taubman and S.-y. Chen and H. Lin and R. Agarwal and M. Athar},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.20.760501},
url = {https://www.biorxiv.org/content/10.64898/2026.10.20.760501v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - FAK Dependent Focal Adhesion Remodeling Drives Arsenical Vesicant Induced Skin Injury
AU - X. Wu
AU - H. Liu
AU - S. Suman
AU - A. Hoover
AU - B. Taubman
AU - S.-y. Chen
AU - H. Lin
AU - R. Agarwal
AU - M. Athar
PY - 2026
DA - 2026/10/20
PB - bioRxiv
DO - 10.64898/2026.10.20.760501
UR - https://www.biorxiv.org/content/10.64898/2026.10.20.760501v1
AB - 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. Highlights: First demonstration that focal adhesion kinase (FAK) is a critical molecular target of chemical vesicants whose dysregulation disrupts epidermal–dermal junctional integrity and initiates micro-vesicant injury. Establishes FAK-mediated junctional disruption as an early pathogenic event that triggers and amplifies subsequent inflammatory and programmed cell-death responses following vesicant exposure. Integrating in vivo genetic and pharmacological approaches, identifies FAK as a mechanistically validated and therapeutically actionable target for development of a mechanism-based medical countermeasure (MCM) against chemical vesicant injury.
SN - 2692-8205
ER -