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It is important to identify influential genes modulating the immune response in sepsis. In this study, we used P\u2010NET, a biologically informed explainable artificial intelligence model, to evaluate the gene importance for sepsis. About 688 important genes were identified, and these genes were enriched in pathways involved in inflammation and immune regulation, such as the PI3K\u2010Akt signalling pathway, necroptosis and the NF\u2010\u03baB signalling pathway. We further selected differentially expressed genes both at bulk and single\u2010cell levels and found TIMP1, GSTO1 and MYL6 exhibited significant different expressions in multiple cell types. Moreover, the expression levels of these 3 genes were correlated with the abundance of important immune cells, such as M\u2010MDSC cells. Further analysis demonstrated that these three genes were highly expressed in sepsis patients with worse outcomes, such as severe, non\u2010survived and shock sepsis patients. Using a drug repositioning strategy, we found navitoclax, curcumin and rotenone could down\u2010regulate and bind to these genes. In conclusion, TIMP1, GSTO1 and MYL6 may serve as promising biomarkers and targets for sepsis treatment.<\/jats:p>","DOI":"10.1111\/1440-1681.70031","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T00:09:53Z","timestamp":1747094993000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Sepsis Important Genes Identification Through Biologically Informed Deep Learning and Transcriptomic Analysis"],"prefix":"10.1111","volume":"52","author":[{"given":"Ruichen","family":"Li","sequence":"first","affiliation":[{"name":"University of Shanghai for Science and Technology  Shanghai China"},{"name":"Naval Medical Center Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiushi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine The First Affiliated Hospital of Shandong First Medical 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