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Helichrysum italicum (HI) is a Mediterranean plant with well-reported use in traditional medicine for a wide range of applications, including digestive and liver disorders, intestinal parasitic infections, wound healing, stomach ache and asthma. However, little is known about the global mechanism behind its pleiotropic activity.The aim of this study was to explain the mechanism behind the previously demonstrated effects of HI and to justify its use in traditional medicine.A microarray-based transcriptome analysis was used to discover the global transcriptional alterations in primary colon fibroblasts after exposure to HI infusion for 6 h and 24 h. In addition, quantitative real-time PCR was used to verify the microarray results.Altogether we identified 217 differentially expressed genes compared to non-treated cells, and only 8 were common to both treatments. Gene ontology analysis revealed that 24 h treatment with HI infusion altered the expression of genes involved in cytoskeletal rearrangement and cell growth, whereas pathway analysis further showed the importance of interleukin signaling and transcriptional regulation by TP53. For the 6 h treatment only the process of hemostasis appeared in the results of both enrichment analyses. In functional assays, HI infusion increased cell migration and decreased blood clotting and prothrombin time.With the careful evaluation of the role of individual genes, especially SERPING1, ARHGAP1, IL33 and CDKN1A, represented in the enriched pathways and processes, we propose the main mode of HI action, which is wound healing. In addition to its indirect prevention of diseases resulting from the impaired barrier integrity, HI also effects inflammation and metabolic processes directly, as it regulates genes such as LRPPRC, LIPA, ABCA12, PRKAR1A and ANXA6.