{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T20:57:22Z","timestamp":1770065842576,"version":"3.49.0"},"reference-count":22,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T00:00:00Z","timestamp":1745366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002858","name":"Postdoctoral Fellowship Program of China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["GZC20231341"],"award-info":[{"award-number":["GZC20231341"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"Postdoctoral Fellowship Program of China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["12024C01001"],"award-info":[{"award-number":["12024C01001"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Beijing Tsinghua Changgung Hospital Fund","award":["GZC20231341"],"award-info":[{"award-number":["GZC20231341"]}]},{"name":"Beijing Tsinghua Changgung Hospital Fund","award":["12024C01001"],"award-info":[{"award-number":["12024C01001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sepsis is a severe systemic response to infection that may lead to the dysfunction of multiple organ systems and may even be life-threatening. Circadian rhythm-related genes (CRDRGs) regulate the circadian clock and affect many physiological processes, including immune responses. In patients with sepsis, circadian rhythms may be disrupted, thus leading to problems such as immune responses. RNA-seq datasets of sepsis and control groups were downloaded from the Gene Expression Omnibus (GEO) database, and two sepsis subtypes were identified based on differentially expressed CRDRGs. Two gene modules related to sepsis diagnosis and subtypes were obtained using the weighted co-expression network (WGCNA) algorithm. Subsequently, using four machine learning algorithms (random forest, support vector machine, a generalized linear model, and xgboost), genes related to sepsis diagnosis were identified from the intersection genes of the two modules, and a diagnostic model was constructed. Single-cell sequencing (scRNA-seq) data were obtained from the GEO database to explore the expression landscape of diagnostic-related genes in different cell types. Finally, an RT-qPCR analysis of diagnosis-related genes confirmed the differences in expression trends between the two groups. Multiple differentially expressed CRDRGs were observed in the sepsis and control groups, and two subtypes were identified based on their expression levels. There were apparent differences in the distribution of samples of the two subtypes in two-dimensional space and the pathways involved. Using multiple machine learning algorithms, the intersection genes in the two most relevant modules of the WGCNA were identified, and a robust diagnostic model was constructed with five genes (ARHGEF18, CHD3, PHC1, SFI1, and SPOCK2). The AUC of this model reached 0.987 on the validation set, showing an excellent prediction performance. In this study, two sepsis subtypes were identified, and a sepsis diagnostic model was constructed via consensus clustering and machine learning algorithms. Five genes were identified as diagnostic markers for sepsis and can thus assist in clinical diagnosis and guide personalized treatment.<\/jats:p>","DOI":"10.3390\/ijms26093993","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T10:40:48Z","timestamp":1745404848000},"page":"3993","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exploring the Role of Circadian Rhythm-Related Genes in the Identification of Sepsis Subtypes and the Construction of Diagnostic Models Based on RNA-seq and scRNA-seq"],"prefix":"10.3390","volume":"26","author":[{"given":"Xuesong","family":"Wang","sequence":"first","affiliation":[{"name":"Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 100084, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhe","family":"Guo","sequence":"additional","affiliation":[{"name":"Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 100084, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziwen","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 100084, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinrui","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 100084, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuxiang","family":"Xia","sequence":"additional","affiliation":[{"name":"Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 100084, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dishan","family":"Wu","sequence":"additional","affiliation":[{"name":"Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 100084, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhong","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 100084, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1097\/CCM.0000000000000742","article-title":"Lactate measurements in sepsis-induced tissue hypoperfusion: Results from the Surviving Sepsis Campaign database","volume":"43","author":"Casserly","year":"2015","journal-title":"Crit. Care Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990\u20132017: Analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Shu, Q., She, H., Chen, X., Zhong, L., Zhu, J., and Fang, L. (2023). Identification and experimental validation of mitochondria-related genes biomarkers associated with immune infiltration for sepsis. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1184126"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Jiang, H., Ren, Y., Yu, J., Hu, S., and Zhang, J. (2023). Analysis of lactate metabolism-related genes and their association with immune infiltration in septic shock via bioinformatics method. Front. Genet., 14.","DOI":"10.3389\/fgene.2023.1223243"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1186\/s12967-023-04499-4","article-title":"A diagnostic model for sepsis-induced acute lung injury using a consensus machine learning approach and its therapeutic implications","volume":"21","author":"Zheng","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1021\/bi5007354","article-title":"Circadian clock, cancer, and chemotherapy","volume":"54","author":"Sancar","year":"2015","journal-title":"Biochemistry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1007\/s00125-019-05059-6","article-title":"Impact of circadian disruption on glucose metabolism: Implications for type 2 diabetes","volume":"63","author":"Mason","year":"2020","journal-title":"Diabetologia"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/S0140-6736(17)32132-3","article-title":"Daytime variation of perioperative myocardial injury in cardiac surgery and its prevention by Rev-Erb\u03b1 antagonism: A single-centre propensity-matched cohort study and a randomised study","volume":"391","author":"Montaigne","year":"2018","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.3109\/07420520903408358","article-title":"Diurnal variation in endotoxin-induced mortality in mice: Correlation with proinflammatory factors","volume":"26","author":"Marpegan","year":"2009","journal-title":"Chronobiol. Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1097\/SHK.0000000000001241","article-title":"Circadian Rhythm Disruption and Sepsis in Severe Trauma Patients","volume":"52","author":"Coiffard","year":"2019","journal-title":"Shock"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/s41577-018-0008-4","article-title":"Clocking in to immunity","volume":"18","author":"Scheiermann","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1097\/CCM.0000000000006135","article-title":"Surviving Sepsis Campaign Research Priorities 2023","volume":"52","author":"Deutschman","year":"2024","journal-title":"Crit. Care Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Wang, X., Guo, Z., Chai, Y., Wang, Z., Liao, H., Wang, Z., and Wang, Z. (2023). Application Prospect of the SOFA Score and Related Modification Research Progress in Sepsis. J. Clin. Med., 12.","DOI":"10.3390\/jcm12103493"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The third international consensus definitions for sepsis and septic shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s13613-021-00833-5","article-title":"Circadian rhythms in septic shock patients","volume":"11","author":"Lachmann","year":"2021","journal-title":"Ann. Intensive Care"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1038\/s41467-021-22961-z","article-title":"Feeding-induced resistance to acute lethal sepsis is dependent on hepatic BMAL1 and FXR signalling","volume":"12","author":"Geiger","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Oliveira, R.A.C., Imparato, D.O., Fernandes, V.G.S., Cavalcante, J.V.F., Albanus, R.D., and Dalmolin, R.J.S. (2021). Reverse Engineering of the Pediatric Sepsis Regulatory Network and Identification of Master Regulators. Biomedicines, 9.","DOI":"10.3390\/biomedicines9101297"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Jensen, I.J., Winborn, C.S., Fosdick, M.G., Shao, P., Tremblay, M.M., Shan, Q., Tripathy, S.K., Snyder, C.M., Xue, H.-H., and Griffith, T.S. (2018). Polymicrobial sepsis influences NK-cell-mediated immunity by diminishing NK-cell-intrinsic receptor-mediated effector responses to viral ligands or infections. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007405"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Fan, Y., Han, Q., Li, J., Ye, G., Zhang, X., Xu, T., and Li, H. (2022). Revealing potential diagnostic gene biomarkers of septic shock based on machine learning analysis. BMC Infect. Dis., 22.","DOI":"10.1186\/s12879-022-07056-4"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1097\/MCC.0000000000001092","article-title":"The role of renin-angiotensin system in sepsis-associated acute kidney injury: Mechanisms and therapeutic implications","volume":"29","author":"Garcia","year":"2023","journal-title":"Curr. Opin. Crit. Care"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Bai, Y., Mi, W., Meng, X., Dong, B., Jiang, Y., Lu, Y., and Yu, Y. (2023). Hydrogen alleviated cognitive impairment and blood-brain barrier damage in sepsis-associated encephalopathy by regulating ABC efflux transporters in a PPAR\u03b1-dependent manner. BMC Neurosci., 24.","DOI":"10.1186\/s12868-023-00795-3"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/vec.13359","article-title":"Defining sepsis in small animals","volume":"34","author":"Cortellini","year":"2024","journal-title":"J. Vet. Emerg. Crit. 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