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Despite significant morbidity and decreased quality of life, there are limited effective treatment options for such a disease. Therefore, identifying causal genes and dysregulated pathways paves the way for novel therapeutic interventions. In the current study, a three-way interaction approach was used to detect dynamic co-expression interactions involved in CRSwNP. In this approach, the internal evolution of the co-expression relation between a pair of genes (X, Y) was captured under a change in the expression profile of a third gene (Z), named the switch gene. Subsequently, the biological relevancy of the statistically significant triplets was confirmed using both gene set enrichment analysis and gene regulatory network reconstruction. Finally, the importance of identified switch genes was confirmed using a random forest model. The results suggested four dysregulated pathways in CRSwNP, including \u201cpositive regulation of intracellular signal transduction\u201d, \u201carachidonic acid metabolic process\u201d, \u201cspermatogenesis\u201d and \u201cnegative regulation of cellular protein metabolic process\u201d. Additionally, the <jats:italic>S100a9<\/jats:italic> as a switch gene together with the gene pair {<jats:italic>Cd14<\/jats:italic>, <jats:italic>Tpd52l1<\/jats:italic>} form a biologically relevant triplet. More specifically, we suggested that <jats:italic>S100a9<\/jats:italic> might act as a potential upstream modulator in toll-like receptor 4 transduction pathway in the major CRSwNP pathologies.<\/jats:p>","DOI":"10.1038\/s41598-024-60205-4","type":"journal-article","created":{"date-parts":[[2024,4,27]],"date-time":"2024-04-27T16:01:49Z","timestamp":1714233709000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["S100a9 might act as a modulator of the Toll-like receptor 4 transduction pathway in chronic rhinosinusitis with nasal polyps"],"prefix":"10.1038","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3524-8589","authenticated-orcid":false,"given":"Nasibeh","family":"Khayer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6081-0353","authenticated-orcid":false,"given":"Maryam","family":"Jalessi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Farhadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Azad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,27]]},"reference":[{"issue":"1","key":"60205_CR1","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1056\/NEJMcp1800215","volume":"381","author":"C Hopkins","year":"2019","unstructured":"Hopkins, C. 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