{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:12:30Z","timestamp":1787026350544,"version":"build-2736575974"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20241798"],"award-info":[{"award-number":["BK20241798"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017962","name":"Jiangsu Commission of Health","doi-asserted-by":"publisher","award":["M2022086"],"award-info":[{"award-number":["M2022086"]}],"id":[{"id":"10.13039\/100017962","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"\n Background<\/jats:title>\n Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Early diagnosis remains challenging due to substantial clinical and biological heterogeneity. CD14 is a central pattern-recognition receptor in innate immune activation, but the downstream network linking CD14 to immunometabolic regulation remains incompletely defined. We aimed to identify CD14-associated blood-based diagnostic biomarkers for sepsis and explore potential regulatory mechanisms.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Whole-blood transcriptomic datasets were retrieved from the Gene Expression Omnibus. GSE236713 was the discovery cohort and GSE65682 the external validation cohort. Candidate genes were identified through overlap of differentially expressed genes between\n CD14<\/jats:italic>\n -high and\n CD14<\/jats:italic>\n -low samples and sepsis-related WGCNA modules. Hub genes were prioritized by protein-protein interaction analysis, and feature genes were identified by LASSO and random forest. Multiple machine learning algorithms were compared, and an artificial neural network (ANN) classifier was established. Clinical associations, immune cell composition (CIBERSORT), and pathway activity (GSEA) were assessed. Mechanistic validation was performed in LPS-stimulated RAW264.7 macrophages using CD14 knockout\/overexpression and SN50-mediated inhibition of NF-\u03baB nuclear translocation.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Five feature genes (\n MMP9<\/jats:italic>\n ,\n PPARG<\/jats:italic>\n ,\n C1QC<\/jats:italic>\n ,\n MS4A4A<\/jats:italic>\n , and\n ARG1<\/jats:italic>\n ) were identified. Among seven algorithms, the ANN achieved the best performance (internal AUC\u00a0=\u00a00.974, external AUC\u00a0=\u00a00.953).\n PPARG<\/jats:italic>\n showed the strongest single-gene diagnostic ability (AUC\u00a0=\u00a00.994) and correlated with SOFA score (\n r<\/jats:italic>\n \u00a0=\u00a00.50,\n P<\/jats:italic>\n \u00a0=\u00a01.5 \u00d7 10\n -<\/jats:sup>\n \u00b2\n 9<\/jats:sup>\n ), and was prioritized as a diagnostic biomarker. In a Cox model,\n PPARG<\/jats:italic>\n was associated with ICU short-term outcome risk (HR\u00a0=\u00a01.64, 95% CI 1.34\u20132.01,\n P<\/jats:italic>\n \u00a0=\u00a01.3 \u00d7 10\n -6<\/jats:sup>\n ). GSEA indicated enrichment of NF-\u03baB-related pathways in samples with low\n PPARG<\/jats:italic>\n expression. CIBERSORT suggested the strongest correlation between\n PPARG<\/jats:italic>\n and monocyte proportion (\n r<\/jats:italic>\n \u00a0=\u00a00.328,\n P<\/jats:italic>\n \u00a0=\u00a01.06 \u00d7 10\n -6<\/jats:sup>\n ).\n In vitro<\/jats:italic>\n , LPS-induced PPARG downregulation was CD14-dependent, and SN50 partially reversed PPARG suppression and reduced TNF-\u03b1 secretion in CD14-overexpressing cells.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n By integrating machine learning with experimental validation, this study prioritized PPARG as a diagnostic biomarker for sepsis and provided supportive evidence for its association with CD14\/NF-\u03baB signaling. These findings offer a basis for developing host-response-based diagnostic signatures and further investigation of PPARG-related immunometabolic regulation in sepsis.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fcimb.2026.1800050","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T04:43:55Z","timestamp":1779943435000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Machine learning identifies PPARG as a diagnostic biomarker for sepsis linked to CD14\/NF-\u03baB signaling: integrated transcriptomics and experimental validation"],"prefix":"10.3389","volume":"16","author":[{"given":"Yingying","family":"Ji","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, The First Affiliated Hospital of Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The First Affiliated Hospital of Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanou","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The First Affiliated Hospital of Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The First Affiliated Hospital of Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The First Affiliated Hospital of Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The First Affiliated Hospital of Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1210\/er.2018-00064","article-title":"Molecular actions of PPAR\u03b1 in lipid metabolism and inflammation","volume":"39","author":"Bougarne","year":"2018","journal-title":"Endocr. 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