Triclosan Exposure Perturbs Skin Lipid Metabolism and Inflammatory Pathways: Insights from Network Toxicology and Multi-Omics Analyses.

Triclosan (TCS) is a synthetic antimicrobial extensively used in personal care products and dermatological formulations, leading to frequent human dermal exposure. Despite its bioaccumulative potential and efficient skin penetration, the mechanisms underlying TCS-induced cutaneous toxicity remain poorly understood. Here, we employed an integrative toxicological framework combining network toxicology, transcriptomics, and untargeted metabolomics to systematically investigate TCS-induced cutaneous injury. Network analysis revealed that TCS-associated targets were significantly enriched in immune and inflammatory signaling pathways, particularly IL-17 signaling and cytokine-cytokine receptor interactions. Consistently, repeated dermal exposure to TCS in mice induced visible skin lesions, including erythema, epidermal hyperplasia, and scaling, accompanied by prominent infiltration of neutrophils and macrophages. Transcriptomic profiling demonstrated robust activation of inflammatory and immune pathways, with marked upregulation of Il1b, Il6, and Tnf. Metabolomic analysis further revealed substantial disruption of skin lipid metabolism, particularly sphingolipid metabolism and unsaturated fatty acid biosynthesis, leading to increased levels of bioactive lipid mediators such as sphinganine-1-phosphate. Integrated analyses indicated strong positive associations between lipid metabolic alterations, inflammatory gene expression, and immune cell infiltration, suggesting potential mechanistic crosstalk between lipid remodeling and inflammation. Collectively, these findings demonstrate that dermal TCS exposure induces coordinated immune activation and lipid metabolic reprogramming, thereby linking antimicrobial exposure to cutaneous inflammatory injury. This study highlights potential skin health risks associated with TCS-containing products and provides important insights for environmental safety assessment and dermatological risk evaluation.