Proteomic profiling and bioinformatics insights into lung tissue damage following whole-body exposure to sulfur mustard vapor

Sulfur mustard (SM) is a chemical warfare agent that causes severe cellular damage by alkylating DNA and proteins, with the skin, eyes, and respiratory system being the most affected. Acute respiratory injury is the primary cause of long-term lung damage following exposure. Despite its long history of use, SM's mechanism of action remains poorly understood, and no effective treatments exist. Proteomics enables systematic identification and characterization of proteins in specific tissues, yet no comprehensive proteomic studies have examined lungs exposed to SM. This study presents the first in vivo, time-resolved proteomic characterization of rat lungs at multiple time points after whole-body exposure to SM vapor (155 μg/L/10 min). Using mass spectrometry, differentially expressed proteins were categorized into four groups reflecting different phases of injury: naive (unexposed), 4 days post-exposure (early acute injury), 1 week post-exposure (advanced acute injury), and 4 weeks post-exposure (recovery). Bioinformatics integration of these data revealed stage-specific molecular pathways involved in inflammation, tissue remodeling, oxidative stress, and immune regulation. Importantly, several identified proteins overlapped with known markers of SM-induced damage in human samples, reinforcing their translational relevance. By linking protein groups to disease associations and drug databases, we proposed a dynamic therapeutic framework tailored to the evolving phases of injury. This included specific regimens and identified FDA-approved drugs that target key proteins. By focusing on proteomic profiling changes in response to SM exposure, this study provides novel insights into SM's mechanism of action and supports the development of targeted treatments customized to each stage of injury. • First temporal in vivo lung proteome after sulfur mustard (SM) vapor exposure. • Novel stage-specific protein groups define acute and recovery phases. • Key proteins overlap with human biomarkers, reinforcing translational value. • Drug database integration reveals FDA-approved drugs for repurposing. • Provides first framework for phase tailored therapies in SM induced lung injury.