Abstract

Sulfur mustard (SM), a hazardous chemical warfare agent, poses severe threats to environmental safety and public health due to its persistent toxicity. While the blistering effects of SM are well documented, its impact on the immune system has aroused increasing concern recently. However, the molecular basis underpinning the immune dysregulation elicited by SM remains elusive. Here we found that systemic SM exposure suppressed regulatory T (Treg) cell differentiation, leading to multiple organ inflammation in mice. Both pharmacological inhibition and genetic disruption of DNA methyltransferase Dnmt3b rescued Treg induction and alleviated inflammatory injury in SM-exposed mice, identifying Dnmt3b as a central mediator of SM immunotoxicity. Exposure to SM markedly increased DNA methylation of Foxp3 by upregulating Dnmt3b and enhancing its binding to the Foxp3 promoter. Notably, oleic acid (OA) accumulated upon SM challenge and acted as a signaling molecule to modulate Treg differentiation in a Dnmt3b-dependent manner. Our work reveals that SM disrupts Treg differentiation by altering OA abundance to promote Dnmt3b-mediated DNA methylation, highlighting Dnmt3b as a compelling therapeutic target and identifying Foxp3 promoter methylation and OA as promising biomarkers for SM immunotoxicity assessment.