{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T02:02:27Z","timestamp":1789524147227,"version":"build-2803163510"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Ulcerative colitis (UC) is a chronic inflammatory bowel disease manifested as persistent mucosal inflammation and immune dysregulation. As key regulators of intestinal immune homeostasis, macrophages are pivotal in the amplification of inflammation and tissue repair in UC. However, the molecular mechanisms associated with ferroptosis in macrophages remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>We integrated single-cell and bulk colonic transcriptomes to map ferroptosis-associated programs in UC macrophages, prioritized candidate regulators using network\/ML frameworks, and performed targeted experimental validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified a ferroptosis-associated transcriptional program enriched in UC macrophages and derived a four-gene signature (HIF1A, S100A8, CYBB, GLS) linked to redox\/iron stress. Among them, CYBB encodes NOX2 (the catalytic subunit of NADPH oxidase), and emerged as a key node associated with enhanced oxidative\/iron stress and coordinated changes in ferroptosis-related markers in macrophages.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study systematically delineates the ferroptosis-associated transcriptional network in macrophages of UC, providing a systems-level framework linking macrophage redox\/iron imbalance to ferroptosis vulnerability in UC and nominating CYBB-centered pathways for mechanistic interrogation and stratification-oriented biomarker development, thereby offering novel theoretical insights for immune metabolism mechanisms and targeted therapies in UC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1758082","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T04:35:04Z","timestamp":1776832504000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Deciphering the macrophage ferroptosis regulatory network: construction of an ulcerative colitis diagnostic model and investigation of the immune microenvironment based on single-cell and transcriptomic data"],"prefix":"10.3389","volume":"17","author":[{"given":"Yifang","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University","place":["Quanzhou, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongchi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University","place":["Quanzhou, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, The Nanping First Affiliated Hospital of Fujian Medical University","place":["Nanping, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yirong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Fujian Medical University","place":["Quanzhou, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenhang","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University","place":["Quanzhou, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinghua","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University","place":["Quanzhou, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiyong","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University","place":["Quanzhou, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.2147\/jir.s534447","article-title":"Macrophage metabolic reprogramming in inflammatory bowel diseases: From pathogenesis to therapy","volume":"18","author":"Zhang","year":"2025","journal-title":"J Inflammation Res"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2021.103017","article-title":"The influence of cytokines on the complex pathology of ulcerative colitis","volume":"21","author":"Nakase","year":"2022","journal-title":"Autoimmun Rev"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(23)00966-2","article-title":"Ulcerative colitis","volume":"402","author":"Le Berre","year":"2023","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/s43556-024-00207-w","article-title":"Ulcerative colitis: Molecular insights and intervention therapy","volume":"5","author":"Liang","year":"2024","journal-title":"Mol BioMed"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1623491","article-title":"Macrophages: Emerging targets for ulcerative colitis","volume":"16","author":"Chen","year":"2025","journal-title":"Front Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1155\/2023\/4373840","article-title":"Identifying macrophage-related genes in ulcerative colitis using weighted coexpression network analysis and machine learning","volume":"2023","author":"Hong","year":"2023","journal-title":"Mediators Inflammation"},{"key":"B7","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1038\/s41419-025-07883-8","article-title":"HIF-1\u03b1 alleviates ferroptosis in ulcerative colitis by regulation of GPX4","volume":"16","author":"Hu","year":"2025","journal-title":"Cell Death Dis"},{"key":"B8","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1038\/s41419-020-2299-1","article-title":"Ferroptosis involves in intestinal epithelial cell death in ulcerative colitis","volume":"11","author":"Xu","year":"2020","journal-title":"Cell Death Dis"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102987","article-title":"MCL attenuates atherosclerosis by suppressing macrophage ferroptosis via targeting KEAP1\/NRF2 interaction","volume":"69","author":"Luo","year":"2024","journal-title":"Redox Biol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2024.112231","article-title":"Upregulation of HMOX1 associated with M2 macrophage infiltration and ferroptosis in proliferative diabetic retinopathy","volume":"134","author":"Zhou","year":"2024","journal-title":"Int Immunopharmacol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-021-01223-x","article-title":"HLF regulates ferroptosis, development and chemoresistance of triple-negative breast cancer by activating tumor cell-macrophage crosstalk","volume":"15","author":"Li","year":"2022","journal-title":"J Hematol Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2016.00301","article-title":"NOX activation by subunit interaction and underlying mechanisms in disease","volume":"10","author":"Rastogi","year":"2016","journal-title":"Front Cell Neurosci"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad965","article-title":"NCBI GEO: Archive for gene expression and epigenomics data sets: 23-year update","volume":"52","author":"Clough","year":"2024","journal-title":"Nucleic Acids Res"},{"key":"B14","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1053\/j.gastro.2013.05.048","article-title":"Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis","volume":"146","author":"Sandborn","year":"2014","journal-title":"Gastroenterology"},{"key":"B15","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1097\/mpg.0000000000001898","article-title":"Molecular comparison of adult and pediatric ulcerative colitis indicates broad similarity of molecular pathways in disease tissue","volume":"67","author":"Li","year":"2018","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat","volume":"12","author":"Jin","year":"2021","journal-title":"Nat Commun"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac935","article-title":"FerrDb V2: Update of the manually curated database of ferroptosis regulators and ferroptosis-disease associations","volume":"51","author":"Zhou","year":"2023","journal-title":"Nucleic Acids Res"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.crmeth.2023.100498","article-title":"hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data","volume":"3","author":"Morabito","year":"2023","journal-title":"Cell Rep Methods"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.41","article-title":"Chemically induced mouse models of intestinal inflammation","volume":"2","author":"Wirtz","year":"2007","journal-title":"Nat Protoc"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1513","DOI":"10.1007\/s12672-025-02891-8","article-title":"CYBB as a potential therapeutic target through influencing ferroptosis and macrophage in ovarian cancer","volume":"16","author":"Ye","year":"2025","journal-title":"Discov Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.m116.731216","article-title":"NADPH oxidases are essential for macrophage differentiation","volume":"291","author":"Xu","year":"2016","journal-title":"J Biol Chem"},{"key":"B22","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/j.bbi.2016.07.158","article-title":"NOX2 drives M1-like microglial\/macrophage activation and neurodegeneration following experimental traumatic brain injury","volume":"58","author":"Kumar","year":"2016","journal-title":"Brain Behav Immun"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1042\/cs20150660","article-title":"NOX2-dependent regulation of inflammation","volume":"130","author":"Singel","year":"2016","journal-title":"Clin Sci (Lond)"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3390\/antiox11122376","article-title":"Colon-targeted eNAMPT-specific peptide systems for treatment of DSS-induced acute and chronic colitis in mouse","volume":"11","author":"Kim","year":"2022","journal-title":"Antioxidants (Basel)"},{"key":"B25","doi-asserted-by":"publisher","first-page":"189","DOI":"10.2139\/ssrn.5292920","article-title":"Macrophage NADPH oxidase inhibition by ultralow-dose dextromethorphan alleviates DSS-induced inflammation and colitis","volume":"239","author":"Li","year":"2025","journal-title":"Free Radic Biol Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2025.02.014","article-title":"S100A8 induces cyclophosphamide-induced alopecia via NCF2\/NOX2-mediated ferroptosis","volume":"230","author":"Xu","year":"2025","journal-title":"Free Radic Biol Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.2147\/jir.s527545","article-title":"Comprehensive analysis of ferroptosis markers in lupus nephritis based on bioinformatics analysis and experimental validation","volume":"18","author":"Zhang","year":"2025","journal-title":"J Inflammation Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.178563","article-title":"NADPH oxidase in B cells and macrophages protects against murine lupus by regulation of TLR7","volume":"9","author":"Gordon","year":"2024","journal-title":"JCI Insight"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1758082\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T04:35:12Z","timestamp":1776832512000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1758082\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,22]]},"references-count":28,"alternative-id":["10.3389\/fimmu.2026.1758082"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1758082","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,22]]},"article-number":"1758082"}}