ABSTRACT: Background：The global prevalence of sensitive skin continues to rise. Although relevant animal models have been established, the mechanisms governing skin inflammation and itch in this condition remain incompletely elucidated. Methods：A mouse model of sensitive skin was established using a combination of tape stripping, capsaicin, and propylene glycol treatment. Transcriptome sequencing (RNA-seq), immunofluorescence staining, and quantitative real-time polymerase chain reaction (qPCR) were employed to explore the molecular mechanisms, with a specific focus on verifying genes associated with inflammation and itch. Results：Mice in the model group exhibited typical hallmarks of sensitive skin, including skin barrier damage, inflammatory cell infiltration, enhanced itch response, and elevated erythema index, confirming the successful establishment of the model. RNA-seq identified 3,460 differentially expressed genes (DEGs), comprising 1,888 upregulated and 1,572 downregulated genes. Among these, multiple DEGs related to itch and inflammation were detected. The model group showed increased infiltration of mast cells, neutrophils, and total leukocytes, along with upregulated expression of itch- and pain-associated genes, particularly those belonging to the TRPV and Mrgpr families. Gene Set Enrichment Analysis (GSEA) revealed high expression of key genes in the cGAS-STING signaling pathway (including cGAS, STING, TBK1, and IRF7) in the skin of model mice. Furthermore, treatment with the STING inhibitor H-151 alleviated sensitive skin symptoms in mice, suggesting that the cGAS-STING pathway is involved in the pathogenesis of sensitive skin. Conclusion：This study identifies molecular changes and cellular pathways associated with inflammation, pain, and itch in the skin of sensitive skin model mice, and demonstrates that the cGAS-STING inflammatory pathway may play a critical role in the development of sensitive skin.
