{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:01:29Z","timestamp":1790773289579,"version":"4.1.0"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017700","name":"Henan Provincial Science and Technology Research Project","doi-asserted-by":"publisher","award":["242102311181"],"award-info":[{"award-number":["242102311181"]}],"id":[{"id":"10.13039\/501100017700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017700","name":"Henan Provincial Science and Technology Research Project","doi-asserted-by":"publisher","award":["232102310190"],"award-info":[{"award-number":["232102310190"]}],"id":[{"id":"10.13039\/501100017700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by epithelial barrier dysfunction, yet reliable epithelial-derived diagnostic biomarkers remain elusive.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We employed an integrative multi-omics approach, combining single-cell RNA sequencing (scRNA-seq) and bulk transcriptomics from public datasets. Epithelial cell-specific signatures were identified and intersected with differentially expressed genes to pinpoint candidate markers. Four machine learning algorithms\u2014LASSO, Random Forest, Support Vector Machine and K-Nearest Neighbor (KNN)\u2014were applied for robust feature selection. The diagnostic model was validated in external cohorts, and its association with the immune microenvironment was assessed using CIBERSORT. Finally, key findings were experimentally confirmed in clinical UC tissues via qPCR, Western blot, and immunohistochemistry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>scRNA-seq revealed significant transcriptional remodeling of epithelial cells in UC. Cross-algorithm analysis consistently identified SPINK5 and SRI as the most robust diagnostic biomarkers. A model built on these two genes demonstrated exceptional performance, with an area under the curve (AUC) &amp;gt; 0.90 in both training and external validation sets. Immune infiltration analysis revealed a pro-inflammatory shift in UC and delineated distinct correlations of SPINK5 and SRI with specific immune cell subsets. Experimental validation confirmed significant upregulation of SPINK5 and downregulation of SRI in UC patient tissues at both the mRNA and protein levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our study underscores the pivotal role of epithelial dysfunction in UC pathogenesis. By integrating multi-omics and machine learning, we have established SPINK5 and SRI as promising candidate diagnostic biomarkers, providing candidate biomarkers with potential utility for UC diagnosis and a basis for future studies on disease stratification.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1797539","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T05:39:59Z","timestamp":1781069999000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Epithelial cell\u2013based multi-omics integration identifies SPINK5 and SRI as novel diagnostic biomarkers for ulcerative colitis"],"prefix":"10.3389","volume":"17","author":[{"given":"Xingwang","family":"Li","sequence":"first","affiliation":[{"name":"Department of General Surgery, The First Affiliated Hospital of Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]},{"name":"Department of General Surgery (Colorectal Surgery), Huaihe Hospital Affiliated to Henan University","place":["Kaifeng, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanzhen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, China"]},{"name":"Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, China"]},{"name":"Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The First Affiliated Hospital of Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]},{"name":"Department of General Surgery (Colorectal Surgery), Huaihe Hospital Affiliated to Henan University","place":["Kaifeng, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuewei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of General Surgery (Colorectal Surgery), Huaihe Hospital Affiliated to Henan University","place":["Kaifeng, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunhou","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of General Surgery (Colorectal Surgery), Huaihe Hospital Affiliated to Henan University","place":["Kaifeng, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuhong","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of General Surgery (Colorectal Surgery), Huaihe Hospital Affiliated to Henan University","place":["Kaifeng, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoming","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Huaihe Hospital Affiliated to Henan University","place":["Kaifeng, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongping","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The First Affiliated Hospital of Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]},{"name":"Department of General Surgery (Colorectal Surgery), Huaihe Hospital Affiliated to Henan University","place":["Kaifeng, China"]},{"name":"Zhongda Hospital, School of Medicine, Advanced Institute for Life and Health, Southeast University","place":["Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1186\/s40001-023-01200-9","article-title":"Predicting diagnostic biomarkers associated with immune infiltration in crohn's disease based on machine learning and bioinformatics","volume":"28","author":"Bao","year":"2023","journal-title":"Eur. J. Med. Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1016\/j.immuni.2019.02.006","article-title":"Anti-commensal IgG drives intestinal inflammation and type 17 immunity in ulcerative colitis","volume":"50","author":"Castro-Dopico","year":"2019","journal-title":"Immunity"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1186\/s12967-024-05934-w","article-title":"Integrating single-cell RNA-seq and machine learning to dissect tryptophan metabolism in ulcerative colitis","volume":"22","author":"Chen","year":"","journal-title":"J. Transl. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s13040-024-00382-0","article-title":"Integrating transcriptomics and proteomics to analyze the immune microenvironment of cytomegalovirus associated ulcerative colitis and identify relevant biomarkers","volume":"17","author":"Chen","year":"","journal-title":"BioData Min."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1186\/s12967-025-07058-1","article-title":"Screening and experimental study of potential biomarkers for ulcerative colitis based on weighted gene co-expression network analysis and machine learning","volume":"23","author":"Chen","year":"2025","journal-title":"J. Transl. Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00281-026-01068-x","article-title":"Paneth cells as orchestrators of epithelial barrier defense and emerging therapeutic targets in inflammatory bowel disease","volume":"48","author":"Erkert","year":"2026","journal-title":"Semin. Immunopathol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1038\/s41419-020-03063-y","article-title":"Sorcin is an early marker of neurodegeneration, Ca2+ dysregulation and endoplasmic reticulum stress associated to neurodegenerative diseases","volume":"11","author":"Genovese","year":"2020","journal-title":"Cell Death Dis."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2535","DOI":"10.1038\/s12276-024-01346-4","article-title":"Sorcin can trigger pancreatic cancer-associated new-onset diabetes through the secretion of inflammatory cytokines such as serpin E1 and CCL5","volume":"56","author":"Gong","year":"2024","journal-title":"Exp. Mol. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1136\/gutjnl-2024-334165","article-title":"Single-cell omics in inflammatory bowel disease: recent insights and future clinical applications","volume":"74","author":"Gudi\u00f1o","year":"2025","journal-title":"Gut"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1534768","DOI":"10.3389\/fimmu.2025.1534768","article-title":"Investigating the molecular mechanisms associated with ulcerative colitis through the application of single-cell combined spatial transcriptome sequencing","volume":"16","author":"Huang","year":"2025","journal-title":"Front. Immunol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2911","DOI":"10.1016\/j.csbj.2024.07.011","article-title":"Decoding the mosaic of inflammatory bowel disease: illuminating insights with single-cell RNA technology","volume":"23","author":"Liu","year":"2024","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1498864","DOI":"10.3389\/fmed.2025.1498864","article-title":"Comprehensive analysis of anoikis-related gene signature in ulcerative colitis using machine learning algorithms","volume":"12","author":"Liu","year":"2025","journal-title":"Front. Med. (Lausanne)"},{"key":"B13","doi-asserted-by":"publisher","first-page":"17562848251362391","DOI":"10.1177\/17562848251362391","article-title":"Identifying inflammatory bowel disease subtypes: a comprehensive exploration of transcriptomic data and machine learning-based approaches","volume":"18","author":"Saini","year":"2025","journal-title":"Ther. Adv. Gastroenterol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"868508","DOI":"10.3389\/fmed.2022.868508","article-title":"Ulcerative colitis: novel epithelial insights provided by single cell RNA sequencing","volume":"9","author":"Serigado","year":"2022","journal-title":"Front. Med. (Lausanne)"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e02014","DOI":"10.1002\/advs.202502014","article-title":"Single-cell transcriptomics unravels growth factor Erv1-Like mediated ferroptosis as a key driver of intestinal epithelial dysfunction in ulcerative colitis","volume":"16","author":"Song","year":"2025","journal-title":"Adv. Sci. (Weinh)"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1142215","DOI":"10.3389\/fimmu.2023.1142215","article-title":"Identification of cuproptosis-associated subtypes and signature genes for diagnosis and risk prediction of Ulcerative colitis based on machine learning","volume":"14","author":"Tang","year":"2023","journal-title":"Front. Immunol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1007\/s00018-025-05870-y","article-title":"Sorcin regulates alveolarization and airway tissue remodeling during lung morphogenesis","volume":"82","author":"Tito","year":"2025","journal-title":"Cell Mol. Life Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1454263","DOI":"10.3389\/fimmu.2024.1454263","article-title":"Evaluating methods for integrating single-cell data and genetics to understand inflammatory disease complexity","volume":"15","author":"Townsend","year":"2024","journal-title":"Front. Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"01235","DOI":"10.1016\/j.cell.2025.10.030","article-title":"Macrophage-targeted immunocytokine leverages myeloid, T, and NK cell synergy for cancer immunotherapy","volume":"19","author":"von Locquenghien","year":"2025","journal-title":"Cell"},{"key":"B20","doi-asserted-by":"publisher","first-page":"15009","DOI":"10.1038\/s41598-024-65481-8","article-title":"Exploration and verification a 13-gene diagnostic framework for ulcerative colitis across multiple platforms via machine learning algorithms","volume":"14","author":"Wang","year":"","journal-title":"Sci. Rep."},{"key":"B21","doi-asserted-by":"publisher","first-page":"5874","DOI":"10.1038\/s41467-024-50048-y","article-title":"Therapeutic potential of the secreted Kazal-type serine protease inhibitor SPINK4 in colitis","volume":"15","author":"Wang","year":"","journal-title":"Nat. Commun."},{"key":"B22","doi-asserted-by":"publisher","first-page":"710","DOI":"10.2174\/0118715303332155240912050838","article-title":"Revealing fibrosis genes as biomarkers of ulcerative colitis: a bioinformatics study based on ScRNA and bulk RNA datasets","volume":"25","author":"Wang","year":"2025","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"B23","doi-asserted-by":"publisher","first-page":"2774","DOI":"10.18632\/aging.205510","article-title":"Machine learning-based B cell-related diagnostic biomarker signature and molecular subtypes characteristic of ulcerative colitis","volume":"16","author":"Wu","year":"2024","journal-title":"Aging (Albany NY)"},{"key":"B24","doi-asserted-by":"publisher","first-page":"148990","DOI":"10.1016\/j.ijbiomac.2025.148990","article-title":"Integrated bulk and single-cell RNA sequencing analysis reveals cuproptosis-related proteins in crohn's disease","volume":"333","author":"Wu","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1186\/s10020-025-01326-y","article-title":"RHBDF2 governs microglial neuroinflammation during cerebral ischemia-reperfusion injury and is positively regulated by the m6A reader YTHDF1","volume":"31","author":"Xu","year":"2025","journal-title":"Mol. Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1038\/s41417-026-01019-6","article-title":"SPINK5 promotes sensitivity to cisplatin by inducing ferroptosis in head and neck carcinoma","author":"Yao","year":"2026","journal-title":"Cancer Gene Ther."},{"key":"B27","doi-asserted-by":"publisher","first-page":"4397","DOI":"10.3748\/wjg.v29.i28.4397","article-title":"Application of single-cell omics in inflammatory bowel disease","volume":"28","author":"Zheng","year":"2023","journal-title":"World J. Gastroenterol."}],"updated-by":[{"DOI":"10.3389\/fphar.2026.1928449","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000}}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1797539\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:34:58Z","timestamp":1790771698000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1797539\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,10]]},"references-count":27,"alternative-id":["10.3389\/fphar.2026.1797539"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1797539","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,10]]},"article-number":"1797539"}}