From Acute Exposure to Chronic Disease: Deciphering the Molecular and microRNA Signature of Sulfur Mustard Toxicity

Abstract

Sulfur mustard (SM) is a potent alkylating agent that causes severe acute injuries to the skin, eyes, and respiratory tract. Its devastating legacy extends decades beyond initial exposure, manifesting as chronic conditions like "mustard lung," skin lesions, and pulmonary fibrosis in survivors of the Iraq war against Iran. The molecular pathogenesis linking acute alkylation damage to these progressive disorders remains a critical enigma.

This review synthesizes contemporary research to map this complex trajectory, detailing the initial cascade of DNA damage, oxidative stress, and necroptosis, followed by sustained inflammation and pro-fibrotic signaling. We particularly focus on the central role of TGF-β/Smad and Trefoil Factor Family 1 (TFF1) in airway remodeling. A major emphasis is placed on epigenetic dysregulation, specifically microRNAs (miRNAs). We consolidate evidence identifying specific miRNAs such as upregulated miR-21 in skin fibrosis and dysregulated urinary miR-9 and miR-143 as promising diagnostic biomarkers. By integrating molecular pathogenesis with cutting-edge biomarker discovery, this review provides a framework for understanding SM's long-term toxicity and highlights potential tools to mitigate the enduring burden on exposed veterans.