{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:37:38Z","timestamp":1790689058714,"version":"4.1.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"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. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Biliary atresia (BA) is one of the most destructive liver and biliary diseases in neonates and is characterized by progressive fibrous inflammatory obstruction of the intrahepatic and extrahepatic bile ducts, ultimately leading to liver fibrosis and liver failure. This study aimed to use integrated bioinformatics methods to identify differentially expressed genes (DEGs) in BA liver tissue, identify key genes, and explore their mechanisms in liver fibrosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We obtained data from the gene expression omnibus (GEO) dataset GSE122340 [171 BA patients and 7 normal controls (NCs)]. DEGs were screened via the limma package, followed by gene ontology (GO)\/kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis. A protein-protein interaction (PPI) network was constructed via STRING and Cytoscape, and core genes were selected via the maximum clique centrality (MCC), maximum neighborhood component (MNC), and degree algorithms from the CytoHubba plugin. Further focus was placed on the key gene EGF-like repeats and discoidin I-like domains 3 (EDIL3) through gene set enrichment analysis (GSEA), expression validation, subcellular localization analysis, and clinical tissue sample validation. To minimize batch effects, we performed ComBat correction on the combined gene expression data of GSE122340 and the validation dataset GSE46960 before interdataset comparison.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified a total of 3706 DEGs, including 2774 upregulated DEGs and 932 downregulated DEGs. The functional enrichment analysis revealed that the DEGs were involved mainly in biological processes such as the cell cycle, DNA replication, and extracellular matrix organization, as well as signaling pathways such as herpes simplex virus infection, phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT), and tumor necrosis factor (TNF). Protein-protein interaction (PPI) network analysis revealed 7 core genes (BRCA1, TOP2A, BRCA2, BUB1B, HSP90AA1, PLK4, and EDIL3), with EDIL3 showing the greatest increase in BA. EDIL3 is located on chromosome 5, and its encoded protein is expressed primarily in the cell membrane and extracellular region. GSEA indicated that high EDIL3 expression was significantly associated with apoptosis and activation of the PI3K-AKT signaling pathway. Clinical sample validation revealed that EDIL3 expression was significantly elevated in BA liver tissue, and its high expression was significantly negatively correlated with the survival rate of patients\u2019 native livers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Discoidin I-like domain 3 is a novel gene with a potentially key role in BA-related liver fibrosis, possibly influencing the proliferation and apoptosis of cholangiocytes by regulating the PI3K-AKT signaling pathway, thereby participating in the occurrence and development of liver fibrosis. This study provides new insights into the molecular mechanisms and potential treatment strategies for BA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2025.1726141","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T06:44:36Z","timestamp":1768977876000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Liver fibrosis in biliary atresia: identification of the key gene EDIL3 via integrated bioinformatics"],"prefix":"10.3389","volume":"12","author":[{"given":"Meng","family":"Kong","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital Affiliated to Shandong University","place":["Jinan, China"]},{"name":"Department of Pediatric Surgery, Jinan Children\u2019s Hospital","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhua","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital Affiliated to Shandong University","place":["Jinan, China"]},{"name":"Department of Pediatric Surgery, Jinan Children\u2019s Hospital","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanyang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital Affiliated to Shandong University","place":["Jinan, China"]},{"name":"Department of Pediatric Surgery, Jinan Children\u2019s Hospital","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongzhen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital Affiliated to Shandong University","place":["Jinan, China"]},{"name":"Department of Pediatric Surgery, Jinan Children\u2019s Hospital","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shisong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital Affiliated to Shandong University","place":["Jinan, China"]},{"name":"Department of Pediatric Surgery, Jinan Children\u2019s Hospital","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1146","DOI":"10.1097\/HEP.0000000000001064","article-title":"Integrative single-cell and spatial transcriptomic analyses identify a pathogenic cholangiocyte niche and TNFRSF12A as a therapeutic target for biliary atresia.","volume":"81","author":"Xiao","year":"2025","journal-title":"Hepatology."},{"key":"B2","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1002\/jpn3.70131","article-title":"Advances in prognostic biomarkers for biliary atresia: current insights and future directions.","volume":"81","author":"Anouti","year":"2025","journal-title":"J Pediatr Gastroenterol Nutr."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1704","DOI":"10.1016\/S0140-6736(09)60946-6","article-title":"Biliary atresia.","volume":"374","author":"Hartley","year":"2009","journal-title":"Lancet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e001023","DOI":"10.1136\/wjps-2025-001023","article-title":"Genetic background and biliary atresia.","volume":"8","author":"Meng","year":"2025","journal-title":"World J Pediatr Surg."},{"key":"B5","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/s41572-024-00533-x","article-title":"Biliary atresia.","volume":"10","author":"Tam","year":"2024","journal-title":"Nat Rev Dis Primers."},{"key":"B6","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/j.cld.2022.03.001","article-title":"Biliary atresia in children: update on disease mechanism, therapies, and patient outcomes.","volume":"26","author":"Antala","year":"2022","journal-title":"Clin Liver Dis."},{"key":"B7","doi-asserted-by":"publisher","first-page":"151474","DOI":"10.1016\/j.sempedsurg.2025.151474","article-title":"Immunology of biliary atresia.","volume":"33","author":"Miller","year":"2024","journal-title":"Semin Pediatr Surg."},{"key":"B8","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1186\/s12887-024-05152-9","article-title":"Mechanism of biliary atresia caused by T follicular helper cells-induced immune injury.","volume":"24","author":"Ji","year":"2024","journal-title":"BMC Pediatr."},{"key":"B9","doi-asserted-by":"publisher","first-page":"21814","DOI":"10.1038\/s41598-023-48591-7","article-title":"SOCS2 inhibits hepatoblastoma metastasis via downregulation of the JAK2\/STAT5 signal pathway.","volume":"13","author":"Lv","year":"2023","journal-title":"Sci Rep."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1624671","DOI":"10.3389\/fped.2025.1624671","article-title":"Research on biliary atresia and epigenetic factors from the perspective of transcriptomics: identification of key genes and experimental validation.","volume":"13","author":"Na","year":"2025","journal-title":"Front Pediatr."},{"key":"B11","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1186\/s12887-025-05893-1","article-title":"Immune and genetic landscapes of biliary atresia: a pathway to precision medicine.","volume":"25","author":"Lv","year":"2025","journal-title":"BMC Pediatr."},{"key":"B12","doi-asserted-by":"publisher","first-page":"760182","DOI":"10.3389\/fgene.2021.760182","article-title":"Identifying biomarkers to predict the prognosis of biliary atresia by weighted gene co-expression network analysis.","volume":"12","author":"Kong","year":"2021","journal-title":"Front Genet."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2025.08.036","article-title":"S1P\/S1PR4 promotes the differentiation of CD8+ tissue-resident memory T cells aggravating bile duct injury in biliary atresia.","author":"Sun","year":"2025","journal-title":"J Hepatol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1016\/j.cellsig.2014.01.003","article-title":"Up-regulation of miR-200b in biliary atresia patients accelerates proliferation and migration of hepatic stellate cells by activating PI3K\/Akt signaling.","volume":"26","author":"Xiao","year":"2014","journal-title":"Cell Signal."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1053\/j.gastro.2019.06.017","article-title":"Gene expression signatures associated with survival times of pediatric patients with biliary atresia identify potential therapeutic agents.","volume":"157","author":"Luo","year":"2019","journal-title":"Gastroenterology."},{"key":"B16","doi-asserted-by":"publisher","first-page":"844575","DOI":"10.3389\/fendo.2022.844575","article-title":"BRCA1: an endocrine and metabolic regulator.","volume":"13","author":"Werner","year":"2022","journal-title":"Front Endocrinol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"115654","DOI":"10.1016\/j.celrep.2025.115654","article-title":"Distinct roles of the two BRCA2 DNA-binding domains in DNA damage repair and replication fork preservation.","volume":"44","author":"Neal","year":"2025","journal-title":"Cell Rep."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1566293","DOI":"10.3389\/fmolb.2025.1566293","article-title":"HJURP modulates cell proliferation and chemoresistance via the MYC\/TOP2A transcriptional axis in gastric cancer.","volume":"12","author":"Li","year":"2025","journal-title":"Front Mol Biosci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"617261","DOI":"10.3389\/fmed.2020.617261","article-title":"Current concepts of biliary atresia and matrix metalloproteinase-7: a review of literature.","volume":"7","author":"Nomden","year":"2020","journal-title":"Front Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1055\/s-0041-1739236","article-title":"Detection of cytomegalovirus infection in infants with biliary atresia: a meta-analysis.","volume":"12","author":"Mohamed","year":"2021","journal-title":"Avicenna J Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1038\/s41586-024-07909-9","article-title":"Mechanism of BRCA1-BARD1 function in DNA end resection and DNA protection.","volume":"634","author":"Ceppi","year":"2024","journal-title":"Nature."},{"key":"B22","doi-asserted-by":"publisher","first-page":"5966","DOI":"10.1038\/s41467-021-26227-6","article-title":"BRCA2 associates with MCM10 to suppress PRIMPOL-mediated repriming and single-stranded gap formation after DNA damage.","volume":"12","author":"Kang","year":"2021","journal-title":"Nat Commun."},{"key":"B23","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.cancergen.2024.10.005","article-title":"Elucidating the prognostic and therapeutic significance of TOP2A in various malignancies.","volume":"289","author":"Liu","year":"2024","journal-title":"Cancer Genet."},{"key":"B24","doi-asserted-by":"publisher","first-page":"6210","DOI":"10.1038\/s41388-021-02021-y","article-title":"Increased BUB1B\/BUBR1 expression contributes to aberrant DNA repair activity leading to resistance to DNA-damaging agents.","volume":"40","author":"Komura","year":"2021","journal-title":"Oncogene."},{"key":"B25","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1159\/000512446","article-title":"BUB1B overexpression is an independent prognostic marker and associated with CD44, p53, and PD-L1 in renal cell carcinoma.","volume":"99","author":"Sekino","year":"2021","journal-title":"Oncology."},{"key":"B26","doi-asserted-by":"publisher","first-page":"102334","DOI":"10.1016\/j.tranon.2025.102334","article-title":"BUB1B promotes cisplatin resistance in gastric cancer via Rad51-mediated DNA damage repair.","volume":"54","author":"Qin","year":"2025","journal-title":"Transl Oncol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2061","DOI":"10.3390\/ijms26052061","article-title":"A comprehensive analysis revealing BUB1B as a potential prognostic and immunological biomarker in lung adenocarcinoma.","volume":"26","author":"Hao","year":"2025","journal-title":"Int J Mol Sci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"639596","DOI":"10.3389\/fcell.2021.639596","article-title":"Plasma HSP90AA1 predicts the risk of breast cancer onset and distant metastasis.","volume":"9","author":"Liu","year":"2021","journal-title":"Front Cell Dev Biol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"4979","DOI":"10.7150\/ijbs.111449","article-title":"PLK4 as a key regulator of neuroblastoma differentiation and a promising therapeutic target.","volume":"21","author":"Tian","year":"2025","journal-title":"Int J Biol Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/s44324-025-00063-4","article-title":"ECM formation and degradation during fibrosis, repair, and regeneration.","volume":"3","author":"Mayorca-Guiliani","year":"2025","journal-title":"NPJ Metab Health Dis."},{"key":"B31","doi-asserted-by":"publisher","first-page":"483","DOI":"10.2174\/1389201020666190408112822","article-title":"Evaluation of changes in the expression pattern of EDIL3 in different grades of endometrial cancer.","volume":"20","author":"Oplawski","year":"2019","journal-title":"Curr Pharm Biotechnol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1347888","DOI":"10.3389\/fphys.2024.1347888","article-title":"Developmental endothelial locus 1: the present and future of an endogenous factor in vessels.","volume":"15","author":"Jiang","year":"2024","journal-title":"Front Physiol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1038\/s41590-018-0249-1","article-title":"DEL-1 promotes macrophage efferocytosis and clearance of inflammation.","volume":"20","author":"Kourtzelis","year":"2019","journal-title":"Nat Immunol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"4054","DOI":"10.3892\/mmr.2017.7122","article-title":"EDIL3 knockdown inhibits retinal angiogenesis through the induction of cell cycle arrest in vitro.","volume":"16","author":"Shen","year":"2017","journal-title":"Mol Med Rep."},{"key":"B35","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1172\/JCI17034","article-title":"Neovascularization of ischemic tissues by gene delivery of the extracellular matrix protein Del-1.","volume":"112","author":"Zhong","year":"2003","journal-title":"J Clin Invest."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1314","DOI":"10.1161\/01.CIR.0000118465.36018.2D","article-title":"Developmental endothelial locus-1 (Del-1), a novel angiogenic protein: its role in ischemia.","volume":"109","author":"Ho","year":"2004","journal-title":"Circulation."},{"key":"B37","doi-asserted-by":"publisher","first-page":"e70862","DOI":"10.1096\/fj.202403088R","article-title":"EDIL3 deficiency attenuates liver fibrosis through inhibiting hepatic stellate cells activation via the integrin \u03b1v\u03b23-ERK1\/2-RUNX2 axis in mash mice.","volume":"39","author":"Wei","year":"2025","journal-title":"FASEB J."},{"key":"B38","doi-asserted-by":"publisher","first-page":"4611","DOI":"10.3748\/wjg.v16.i36.4611","article-title":"High expression level of EDIL3 in HCC predicts poor prognosis of HCC patients.","volume":"16","author":"Sun","year":"2010","journal-title":"World J Gastroenterol."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2025.1726141\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T06:44:40Z","timestamp":1768977880000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2025.1726141\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,21]]},"references-count":38,"alternative-id":["10.3389\/fmed.2025.1726141"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2025.1726141","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,21]]},"article-number":"1726141"}}