{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T09:21:21Z","timestamp":1789723281411,"version":"4.0.1"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,10,22]],"date-time":"2024-10-22T00:00:00Z","timestamp":1729555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005046","name":"Natural Science Foundation of Heilongjiang Province","doi-asserted-by":"publisher","award":["ZD2022H005"],"award-info":[{"award-number":["ZD2022H005"]}],"id":[{"id":"10.13039\/501100005046","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Ustekinumab (UST), a biologic against interleukin (IL)-12\/23, is commonly used to treat Crohn\u2019s disease (CD). Myofibroblast (MF) is known as one of the most important factors causing intestinal fibrosis, and UST has been reported to alleviate this condition. However, the genetic mechanisms underlying UST\u2019s effects on CD remain unclear. This study uses bioinformatics tools to analyze the genes and potential pathways affected by UST in CD, with a focus on its anti-fibrosis effects, providing insights into new therapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The data downloaded from the Gene Expression Omnibus (GEO) database were analyzed to screen for differentially expressed genes (DEGs). Various machine learning strategies, including the least absolute shrinkage and selection operator (LASSO), support vector machine (SVM), and random forest (RF), were employed to screen for key genes among the DEGs. Functional and pathway enrichment analyses were conducted, and key genes associated with myofibroblast (MF) activity were screened. Finally, endoscopic surgical specimens from CD patients and healthy participants were collected to assess the expression levels of collagen and key genes in intestinal tissues using hematoxylin\u2013eosin (H&amp;amp;E), Masson staining, and immunohistochemistry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 1,341 DEGs associated with CD were identified. Among them, 738 genes showed low expression in healthy populations but high expression in patients with CD, reduced expression after the treatment of UST. In contrast, 603 genes exhibited high expression in healthy individuals, showed low expression in CD patients, and increased expression after UST treatment. Functional and pathway analysis showed that DEGs were mainly concentrated in response to foreign biological stimuli and bacterial-derived molecules. DEGs are mainly enriched in chemokines, TNF, IL-17, and other signaling pathways. Seven key genes were identified: NCRNA00236, LOC730101, ORP3, XG, UBFD1, KDELC1, and RBP7. Single-cell analysis revealed that KDELC1 was closely related to MF activity. MFs with high KDELC1 expression were significantly enriched in biological functions, signaling pathways, and metabolic processes that promote fibrosis. The experiment showed that UST treatment helped maintain the integrity of intestinal tissue structure, reducing the expression levels of collagen I, KDELC1, and the severity of intestinal fibrosis. The functional and pathway analysis reiterated that DEGs were largely focused on responses to foreign biological stimuli and bacterial-derived molecules, as well as signaling pathways such as chemokines, TNF, and IL-17. Of the identified genes, KDELC1 showed a particularly strong correlation with MF activity in single-cell analysis (R\u2009=\u20090.33,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20093.2e-07). MFs with high KDELC1 expression were closely linked to pathways promoting fibrosis progression, including TGF-\n                      <jats:italic>\u03b2<\/jats:italic>\n                      , epithelial-mesenchymal transformation, TNF\/NF-\u03baB, and related metabolic pathways such as vitamin B6 and arginine.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>KDELC1 plays a key role in regulating multiple biological functions, including signaling pathways related to MF. UST alleviates intestinal fibrosis by targeting KDELC1, thereby influencing intramuscular fat metabolism and intercellular communication.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2024.1476592","type":"journal-article","created":{"date-parts":[[2024,10,22]],"date-time":"2024-10-22T00:42:16Z","timestamp":1729557736000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Ustekinumab affects myofibroblast metabolism to alleviate intestinal fibrosis by targeting KDELC1 in Crohn\u2019s disease through multi-machine learning combined with single-cell sequencing analysis"],"prefix":"10.3389","volume":"11","author":[{"given":"Su","family":"Ma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongming","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhonglin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyu","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomei","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,10,22]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2769","DOI":"10.1016\/S0140-6736(17)32448-0","article-title":"Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies","volume":"390","author":"Ng","year":"2017","journal-title":"Lancet"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1038\/s41575-021-00543-0","article-title":"Revisiting fibrosis in inflammatory bowel disease: the gut thickens","volume":"19","author":"D\u2019Alessio","year":"2022","journal-title":"Nat Rev Dis Primers"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1136\/gutjnl-2018-318081","article-title":"Assessment of Crohn\u2019s disease-associated small bowel strictures and fibrosis on cross-sectional imaging: a systematic review","volume":"68","author":"Bettenworth","year":"2019","journal-title":"Gut"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1053\/j.gastro.2016.09.047","article-title":"Mechanisms, management, and treatment of fibrosis in patients with inflammatory bowel diseases","volume":"152","author":"Rieder","year":"2017","journal-title":"Gastroenterology"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1111\/apt.15750","article-title":"Systematic review: medical therapy for fibrostenosing Crohn\u2019s disease","volume":"51","author":"Lu","year":"2020","journal-title":"Aliment Pharmacol Ther"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"845078","DOI":"10.3389\/fphys.2022.845078","article-title":"The molecular mechanisms of intestinal inflammation and fibrosis in Crohn\u2019s disease","volume":"13","author":"Hayashi","year":"2022","journal-title":"Front Physiol"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1111\/apt.16135","article-title":"Validating the positivity thresholds of drug-tolerant anti-infliximab and anti-adalimumab antibody assays","volume":"53","author":"Nice","year":"2021","journal-title":"Aliment Pharmacol Ther"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1080\/14712598.2023.2198086","article-title":"Efficacious dosing regimens for anti-TNF therapies in inflammatory bowel disease: where do we stand?","volume":"23","author":"Anjie","year":"2023","journal-title":"Expert Opin Biol Ther"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1007\/s12328-020-01242-0","article-title":"Ustekinumab is effective against small bowel lesions in Crohn\u2019s disease: two case reports","volume":"14","author":"Murate","year":"2021","journal-title":"Clin J Gastroenterol"},{"key":"ref10","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":"ref11","doi-asserted-by":"publisher","first-page":"18027","DOI":"10.1038\/s41598-020-74999-6","article-title":"Serum adipokines as non-invasive biomarkers in Crohn\u2019s disease","volume":"10","author":"Ortega Moreno","year":"2020","journal-title":"Sci Rep"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1093\/ecco-jcc\/jjz153","article-title":"The influence of microscopic inflammation at resection margins on early postoperative endoscopic recurrence after ileocaecal resection for Crohn\u2019s disease","volume":"14","author":"Poredska","year":"2020","journal-title":"J Crohns Colitis"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1093\/ecco-jcc\/jjw126","article-title":"Smooth muscle hyperplasia\/hypertrophy is the most prominent histological change in Crohn\u2019s fibrostenosing bowel strictures: a semiquantitative analysis by using a novel histological grading scheme","volume":"11","author":"Chen","year":"2017","journal-title":"J Crohns Colitis"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1016\/j.immuni.2023.01.002","article-title":"The landscape of immune dysregulation in Crohn\u2019s disease revealed through single-cell transcriptomic profiling in the ileum and colon","volume":"56","author":"Kong","year":"2023","journal-title":"Immunity"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1111\/imr.12974","article-title":"Novel mechanisms and clinical trial endpoints in intestinal fibrosis","volume":"302","author":"Wang","year":"2021","journal-title":"Immunol Rev"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.1016\/j.surg.2020.11.039","article-title":"Increased proinflammatory cytokines in mesenteric fat in major surgery and Crohn's disease","volume":"169","author":"Seifarth","year":"2021","journal-title":"Surgery"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"126","DOI":"10.3389\/fmed.2017.00126","article-title":"The role of cytokines in the fibrotic responses in Crohn\u2019s disease","volume":"4","author":"Curciarello","year":"2017","journal-title":"Front Med (Lausanne)"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1080\/19490976.2019.1629235","article-title":"Lipopolysaccharides modulate intestinal epithelial permeability and inflammation in a species-specific manner","volume":"11","author":"Stephens","year":"2020","journal-title":"Gut Microbes"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1002\/ptr.6866","article-title":"The role of medicinal products in the treatment of inflammatory bowel diseases (IBD) through inhibition of TLR4\/NF-kappaB pathway","volume":"35","author":"Dejban","year":"2021","journal-title":"Phytother Res"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"E8395","DOI":"10.1073\/pnas.1804005115","article-title":"Two novel protein O-glucosyltransferases that modify sites distinct from POGLUT1 and affect notch trafficking and signaling","volume":"115","author":"Takeuchi","year":"2018","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"100906","DOI":"10.1016\/j.bbrep.2020.100906","article-title":"Notch and TNF-\u03b1 signaling promote cytoplasmic accumulation of OLFM4 in intestinal epithelium cells and exhibit a cell protective role in the inflamed mucosa of IBD patients","volume":"25","author":"Kuno","year":"2021","journal-title":"Biochem Biophys Rep"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"101055","DOI":"10.1016\/j.jbc.2021.101055","article-title":"POGLUT2 and POGLUT3 O-glucosylate multiple EGF repeats in fibrillin-1,-2, and LTBP1 and promote secretion of fibrillin-1","volume":"297","author":"Williamson","year":"2021","journal-title":"J Biol Chem"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.matbio.2019.06.006","article-title":"The role of fibrillin and microfibril binding proteins in elastin and elastic fibre assembly","volume":"84","author":"Godwin","year":"2019","journal-title":"Matrix Biol"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.semcdb.2018.07.016","article-title":"Fibrillin microfibrils and elastic fibre proteins: functional interactions and extracellular regulation of growth factors","volume":"89","author":"Thomson","year":"2019","journal-title":"Semin Cell Dev Biol"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1042\/BST20210850","article-title":"Identification, function, and biological relevance of POGLUT2 and POGLUT3","volume":"50","author":"Williamson","year":"2022","journal-title":"Biochem Soc Trans"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"317","DOI":"10.3389\/fgene.2019.00317","article-title":"Single-cell RNA-seq technologies and related computational data analysis","volume":"10","author":"Chen","year":"2019","journal-title":"Front Genet"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1180","DOI":"10.1053\/j.gastro.2023.07.014","article-title":"Stricturing Crohn\u2019s disease single-cell RNA sequencing reveals fibroblast heterogeneity and intercellular interactions","volume":"165","author":"Mukherjee","year":"2023","journal-title":"Gastroenterology"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1093\/ecco-jcc\/jjz147","article-title":"Cadherin-11 is a regulator of intestinal fibrosis","volume":"14","author":"Franz\u00e8","year":"2020","journal-title":"J Crohns Colitis"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.1016\/j.cell.2019.08.008","article-title":"Single-cell analysis of Crohn\u2019s disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy","volume":"178","author":"Martin","year":"2019","journal-title":"Cell"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"100056","DOI":"10.1016\/j.mbplus.2020.100056","article-title":"Extracellular matrix remodeling associated with bleomycin-induced lung injury supports pericyte-to-myofibroblast transition","volume":"10","author":"Hannan","year":"2021","journal-title":"Matrix Biol Plus"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"107857","DOI":"10.1016\/j.celrep.2020.107857","article-title":"GM-CSF calibrates macrophage defense and wound healing programs during intestinal infection and inflammation","volume":"32","author":"Castro-Dopico","year":"2020","journal-title":"Cell Rep"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/bs.ircmb.2022.01.003","article-title":"Macrophage control of Crohn\u2019s disease","volume":"367","author":"Tai","year":"2022","journal-title":"Int Rev Cell Mol Biol"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1186","DOI":"10.1093\/ecco-jcc\/jjz039","article-title":"The oxysterol synthesising enzyme CH25H contributes to the development of intestinal fibrosis","volume":"13","author":"Raselli","year":"2019","journal-title":"J Crohns Colitis"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1241262","DOI":"10.3389\/fimmu.2023.1241262","article-title":"Research progress on the mechanism of cholesterol-25-hydroxylase in intestinal immunity","volume":"14","author":"Zhong","year":"2023","journal-title":"Front Immunol"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s13062-020-00280-5","article-title":"Pathophysiology of Crohn\u2019s disease inflammation and recurrence","volume":"15","author":"Petagna","year":"2020","journal-title":"Biol Direct"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1053\/j.gastro.2022.05.050","article-title":"Metabolome changes with diet-induced remission in pediatric Crohn\u2019s disease","volume":"163","author":"Ghiboub","year":"2022","journal-title":"Gastroenterology"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1111\/j.1572-0241.2003.07160.x","article-title":"Low vitamin B6 plasma levels, a risk factor for thrombosis, in inflammatory bowel disease: role of inflammation and correlation with acute phase reactants","volume":"98","author":"Saibeni","year":"2003","journal-title":"Am J Gastroenterol"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1038\/s41430-023-01324-5","article-title":"A retrospective analysis of vitamin B6 deficiency and associated changes of gut microbes in Crohn\u2019s disease","volume":"77","author":"Feng","year":"2023","journal-title":"Eur J Clin Nutr"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"66","DOI":"10.3389\/fcimb.2019.00066","article-title":"Dietary arginine regulates severity of experimental colitis and affects the colonic microbiome","volume":"9","author":"Singh","year":"2019","journal-title":"Front Cell Infect Microbiol"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/s41564-018-0306-4","article-title":"Gut microbiome structure and metabolic activity in inflammatory bowel disease","volume":"4","author":"Franzosa","year":"2019","journal-title":"Nat Microbiol"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"jjw158","DOI":"10.1093\/ecco-jcc\/jjw158","article-title":"Faecal and serum metabolomics in paediatric inflammatory bowel disease","volume":"11","author":"Kolho","year":"2017","journal-title":"J Crohns Colitis"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"2157","DOI":"10.1007\/s10620-012-2127-2","article-title":"Serum metabolic profiling in inflammatory bowel disease","volume":"57","author":"Williams","year":"2012","journal-title":"Dig Dis Sci"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/s11306-017-1311-y","article-title":"Alterations in lipid, amino acid, and energy metabolism distinguish Crohn\u2019s disease from ulcerative colitis and control subjects by serum metabolomic profiling","volume":"14","author":"Scoville","year":"2018","journal-title":"Metabolomics"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1751","DOI":"10.1007\/s10238-022-00931-z","article-title":"Untargeted metabolomics identifies potential serum biomarkers associated with Crohn\u2019s disease","volume":"23","author":"Chen","year":"2023","journal-title":"Clin Exp Med"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"4506","DOI":"10.1038\/s41467-023-40156-6","article-title":"Macrophage and neutrophil heterogeneity at single-cell spatial resolution in human inflammatory bowel disease","volume":"14","author":"Garrido-Trigo","year":"2023","journal-title":"Nat Commun"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1038\/s43588-023-00464-9","article-title":"Single-cell meta-analysis of inflammatory bowel disease with scIBD","volume":"3","author":"Nie","year":"2023","journal-title":"Nat Comput Sci"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.matbio.2022.09.001","article-title":"Human intestinal myofibroblasts deposited collagen VI enhances adhesiveness for T cells--a novel mechanism for maintenance of intestinal inflammation","volume":"113","author":"Lin","year":"2022","journal-title":"Matrix Biol"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1080\/00365521.2016.1256426","article-title":"CD99 refers to the activity of inflammatory bowel disease","volume":"52","author":"Zhou","year":"2017","journal-title":"Scand J Gastroenterol"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.jcmgh.2020.01.009","article-title":"CD74 signaling links inflammation to intestinal epithelial cell regeneration and promotes mucosal healing","volume":"10","author":"Farr","year":"2020","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1038\/nm1567","article-title":"MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment","volume":"13","author":"Bernhagen","year":"2007","journal-title":"Nat Med"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.cellsig.2019.01.006","article-title":"Evolving complexity of MIF signaling","volume":"57","author":"Jankauskas","year":"2019","journal-title":"Cell Signal"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"537","DOI":"10.26402\/jpp.2021.4.05","article-title":"Efficacy of ustekinumab in the treatment of patients with Crohn\u2019s disease with failure to previous conventional or biologic therapy: a prospective observational real-life study","volume":"72","author":"Miranda","year":"2021","journal-title":"J Physiol Pharmacol"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2024.1476592\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,22]],"date-time":"2024-10-22T00:42:18Z","timestamp":1729557738000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2024.1476592\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,22]]},"references-count":52,"alternative-id":["10.3389\/fmed.2024.1476592"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2024.1476592","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,22]]},"article-number":"1476592"}}