{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T03:21:11Z","timestamp":1785295271470,"version":"3.55.0"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T00:00:00Z","timestamp":1741219200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Monocytes represent a vital cellular subpopulation in the peripheral blood, crucial in the progression of sepsis. Nonetheless, the prognostic role and precise function of monocytes in sepsis are still inadequately understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Single-cell transcriptomic sequencing and bioinformatics analysis were performed on peripheral blood samples from septic patients to identify key molecules in cell subsets. Subsequently, the expression pattern of this molecule was validated through diverse biological experiments, encompassing quantitative RT-PCR, western blotting, and immunofluorescence. Finally, the functionality of this molecule was evaluated using its specific agonist.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 22 monocytes-related biomarkers were identified from single-cell and bulk RNA-seq analyses. Initially, LASSO analysis was performed to derive a prognostic signature composed of 4 key genes, including <jats:italic>CD14<\/jats:italic>, <jats:italic>CTSS<\/jats:italic>, <jats:italic>CXCL8<\/jats:italic> and <jats:italic>THBS1<\/jats:italic>. Subsequently, mendelian randomization and survival analysis demonstrated that only <jats:italic>CTSS<\/jats:italic> showed crucially protective role in sepsis development and prognosis. Next, <jats:italic>CTSS<\/jats:italic> was confirmed to be lower expressed in peripheral monocytes of septic patients. Inflammatory markers (<jats:italic>p<\/jats:italic> &amp;lt; 0.05) and migration ability of LPS-activated monocytes were significantly reduced after <jats:italic>CTSS<\/jats:italic> agonist. In addition, <jats:italic>CTSS<\/jats:italic> agonist decreased the pulmonary tissue monocyte\/macrophages infiltration in septic mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Monocyte marker <jats:italic>CTSS<\/jats:italic> represent a promising target for the diagnosis and prognosis evaluation of sepsis and plays a critical role in monocytes activation, tissue inflammatory response and macrophages infiltration. Thus, <jats:italic>CTSS<\/jats:italic> agonist probably serves as new drug for clinical protection against sepsis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2025.1531125","type":"journal-article","created":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T05:10:55Z","timestamp":1741237855000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Multi-omics analysis reveals that low cathepsin S expression aggravates sepsis progression and worse prognosis via inducing monocyte polarization"],"prefix":"10.3389","volume":"15","author":[{"given":"Xiao-Ting","family":"Luo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Rong","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen-Dong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Hong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/s41590-018-0276-y","article-title":"Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage","volume":"20","author":"Aran","year":"2019","journal-title":"Nat. Immunol."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24076234","article-title":"Thiosulfinate-enriched allium sativum extract exhibits differential effects between healthy and sepsis patients: the implication of HIF-1\u03b1","volume":"24","author":"Avenda\u00f1o-Ortiz","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.it.2012.09.004","article-title":"The inflammatory response in sepsis","volume":"34","author":"Bosmann","year":"2013","journal-title":"Trends Immunol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1111\/imr.12499","article-title":"The immune system\u2019s role in sepsis progression, resolution, and long-term outcome","volume":"274","author":"Delano","year":"2016","journal-title":"Immunol. Rev."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1925","DOI":"10.1001\/jama.2017.17219","article-title":"Mendelian randomization","volume":"318","author":"Emdin","year":"2017","journal-title":"Jama"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1156","DOI":"10.1016\/j.ajpath.2014.11.026","article-title":"Selective cathepsin S inhibition attenuates atherosclerosis in apolipoprotein E-deficient mice with chronic renal disease","volume":"185","author":"Figueiredo","year":"2015","journal-title":"Am. J. Pathol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1126\/science.1178331","article-title":"Development of monocytes, macrophages, and dendritic cells","volume":"327","author":"Geissmann","year":"2010","journal-title":"Science"},{"key":"B8","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1038\/nri3552","article-title":"Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy","volume":"13","author":"Hotchkiss","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1038\/s41592-019-0619-0","article-title":"Fast, sensitive and accurate integration of single-cell data with Harmony","volume":"16","author":"Korsunsky","year":"2019","journal-title":"Nat. Methods"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1635","DOI":"10.1681\/asn.2015020208","article-title":"Cathepsin S cleavage of protease-activated receptor-2 on endothelial cells promotes microvascular diabetes complications","volume":"27","author":"Kumar Vr","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinf."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/4235909","article-title":"Monocytes undergo functional reprogramming to generate immunosuppression through HIF-1\u03b1 Signaling pathway in the late phase of sepsis","volume":"2020","author":"Li","year":"2020","journal-title":"Mediators Inflammation"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.1016\/s0140-6736(20)30920-x","article-title":"SARS-CoV-2 and viral sepsis: observations and hypotheses","volume":"395","author":"Li","year":"2020","journal-title":"Lancet"},{"key":"B14","doi-asserted-by":"publisher","first-page":"5019","DOI":"10.1167\/iovs.09-4523","article-title":"Increased expression of cathepsins and obesity-induced proinflammatory cytokines in lacrimal glands of male NOD mouse","volume":"51","author":"Li","year":"2010","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2022.937303","article-title":"Bulk RNA sequencing with integrated single-cell RNA sequencing identifies BCL2A1 as a potential diagnostic and prognostic biomarker for sepsis","volume":"10","author":"Li","year":"2022","journal-title":"Front. Public Health"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2023.e17764","article-title":"Peripheral immune cell death in sepsis based on bulk RNA and single-cell RNA sequencing","volume":"9","author":"Liu","year":"2023","journal-title":"Heliyon"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.1007\/s00134-020-06106-2","article-title":"Epidemiology and burden of sepsis acquired in hospitals and intensive care units: a systematic review and meta-analysis","volume":"46","author":"Markwart","year":"2020","journal-title":"Intensive Care Med."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3390\/biom11071011","article-title":"Inflammation and cell death of the innate and adaptive immune system during sepsis","volume":"11","author":"Nedeva","year":"2021","journal-title":"Biomolecules"},{"key":"B19","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1186\/s12974-023-02943-2","article-title":"M2 macrophage-derived cathepsin S promotes peripheral nerve regeneration via fibroblast-Schwann cell-signaling relay","volume":"20","author":"Oshima","year":"2023","journal-title":"J. Neuroinflamm."},{"key":"B20","doi-asserted-by":"publisher","first-page":"4403","DOI":"10.1074\/jbc.271.8.4403","article-title":"Expression of rat cathepsin S in phagocytic cells","volume":"271","author":"Petanceska","year":"1996","journal-title":"J. Biol. Chem."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1180338","article-title":"Diagnostic value of serum cathepsin S in type 2 diabetic kidney disease","volume":"14","author":"Ren","year":"2023","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B22","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/s0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1133145","article-title":"Single-cell transcriptomics reveals immune infiltrate in sepsis","volume":"14","author":"Tu","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e27379","article-title":"Identification of immune characteristic biomarkers and therapeutic targets in cuproptosis for sepsis by integrated bioinformatics analysis and single-cell RNA sequencing analysis","volume":"10","author":"Wang","year":"2024","journal-title":"Heliyon"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1219","DOI":"10.1016\/j.ygeno.2021.01.026","article-title":"Single-cell RNA sequencing reveals the sustained immune cell dysfunction in the pathogenesis of sepsis secondary to bacterial pneumonia","volume":"113","author":"Wang","year":"2021","journal-title":"Genomics"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.804250","article-title":"Specific interleukin-1 inhibitors, specific interleukin-6 inhibitors, and GM-CSF blockades for COVID-19 (at the edge of sepsis): A systematic review","volume":"12","author":"Wang","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.brainres.2008.07.067","article-title":"Upregulation of cathepsin S in the aging and pathological nervous system of mice","volume":"1232","author":"Wendt","year":"2008","journal-title":"Brain Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1016\/j.bbi.2022.11.001","article-title":"Single-cell RNA sequencing of peripheral blood reveals that monocytes with high cathepsin S expression aggravate cerebral ischemia-reperfusion injury","volume":"107","author":"Xie","year":"2023","journal-title":"Brain Behav. Immun."},{"key":"B29","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics"},{"key":"B30","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1053\/j.gastro.2023.05.039","article-title":"Macrophage-derived cathepsin S remodels the extracellular matrix to promote liver fibrogenesis","volume":"165","author":"Zuo","year":"2023","journal-title":"Gastroenterology"}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2025.1531125\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T05:10:58Z","timestamp":1741237858000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2025.1531125\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,6]]},"references-count":30,"alternative-id":["10.3389\/fcimb.2025.1531125"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2025.1531125","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,6]]},"article-number":"1531125"}}