15(S)-HETE induces immune-related transcriptional changes in fibroblasts

Background: 15(S)-HETE, a bioactive lipid mediator derived from arachidonic acid, is closely associated with eosinophilic inflammation and recurrence in chronic rhinosinusitis with nasal polyps (CRSwNP). Nevertheless, its impact on fibroblast-associated transcriptional regulation remains poorly characterized. Objective: To characterize the transcriptional and immunologic alterations in fibroblasts following 15(S)-HETE exposure. Methods: Human fibroblasts (MRC-5) were exposed to either 15(S)-HETE or a dimethyl sulfoxide vehicle control before RNA sequencing. Differential expression analysis was combined with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway annotation to characterize functional alterations. Pathway-level transcriptional changes were additionally explored using gene set enrichment analysis and weighted gene co-expression network analysis. Fibroblast viability was further assessed with a Cell Counting Kit-8 assay. Results: Transcriptomic profiling of the 15(S)-HETE-treated group revealed 96 differentially expressed genes, consisting of 54 upregulated and 42 downregulated genes. Upregulated genes were enriched in cytokine-related and inflammatory pathways, particularly interleukin-17 and tumor necrosis factor signaling. In contrast, downregulated genes were mainly involved in interferon-mediated antiviral responses. Gene set enrichment analysis further revealed significant suppression of interferon-α and interferon-γ response signatures. Weighted Gene Co-expression Network Analysis identified inflammation-related gene modules associated with 15(S)-HETE stimulation, in which CXCL1 was upregulated. In addition, 15(S)-HETE treatment significantly increased fibroblast viability. Conclusion: 15(S)-HETE was associated with changes in fibroblast transcriptional programs, including reduced interferon-related signatures and increased cytokine signaling. These findings suggest a potential role for 15(S)-HETE in fibroblast-associated immune regulation relevant to CRSwNP.