Sulfur mustard exposure induces inflammatory injury by Dnmt3b-mediated DNA methylation via oleic acid accumulation in Treg cells

  • Chem Biol Interact. 2026 Jul 25:435:112177. doi: 10.1016/j.cbi.2026.112177.
Yunrui Sun  1 ,  Xianrui Jiang  2 ,  Jinfeng Cen  1 ,  Qinyun Shi  3 ,  Linling He  4 ,  Xingrong Du  4 ,  Qingqiang Xu  1 ,  Hua Xu  5 ,  Kai Xiao  6 ,  Songling Li  7
Affiliations
  • 1. Lab of Toxicology and Pharmacology, Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China.
  • 2. School of Pharmacy, Naval Medical University, Shanghai, 200433, China.
  • 3. Laboratory of Toxicant Analysis, Academy of Military Medical Sciences, Beijing, 100850, China.
  • 4. Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 200438, China.
  • 5. Laboratory of Toxicant Analysis, Academy of Military Medical Sciences, Beijing, 100850, China. Electronic address: [email protected].
  • 6. Lab of Toxicology and Pharmacology, Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China. Electronic address: [email protected].
  • 7. Lab of Toxicology and Pharmacology, Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China. Electronic address: [email protected].
PMID: 42208724 DOI: 10.1016/j.cbi.2026.112177
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.

Keywords
DNA methylation; Dnmt3b; Oleic acid; regulatory T cells; sulfur mustard.
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