{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T20:22:19Z","timestamp":1785270139694,"version":"3.55.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:00:00Z","timestamp":1765152000000},"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>Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal interstitial lung disease marked by progressive extracellular matrix accumulation and irreversible lung architecture remodeling. Oxidative stress (OS) plays a crucial role in IPF pathogenesis, yet its role across distinct cellular compartments and tissue microenvironments remains incompletely characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (stRNA-seq), and bulk RNA-seq datasets to comprehensively characterize oxidative stress activity across cellular and tissue scales in IPF lungs. Oxidative stress scores were calculated using multiple enrichment algorithms, and machine learning models (LASSO, Random Forest, Boruta, Bayesian, LVQ, Treebag) were applied to identify robust OS-related diagnostic biomarkers. Expression patterns were validated in public datasets and a bleomycin-induced C57BL\/6 mouse model. Cell-cell communication and gene regulatory pathways were further explored using CellChat and pseudotime trajectory analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Oxidative stress activity was significantly elevated in IPF lung tissue and specifically enriched in basal cells. Among 71 candidate OS-related genes, SCPEP1 emerged as the most robust biomarker, consistently upregulated across multiple datasets and experimental validation, with an AUC of 0.857 in the training cohort. SCPEP1 expression was spatially confined to airway-adjacent regions and highly specific to basal cells. SCPEP1\n                      <jats:sup>+<\/jats:sup>\n                      basal cells exhibited transcriptional reprogramming enriched in Wnt signaling and developmental pathways, dynamic expression during early pseudotime progression, and engaged in multifaceted interactions with immune and stromal cells through pro-fibrotic and inflammatory signaling axes such as MIF-CD74, MDK-NCL, and ICAM1-ITGAL. Translationally, these findings may help prioritize redox-sensitive pathways and ligand\u2013receptor interactions for further investigation. While SCPEP1 appears to be a promising candidate, its potential for patient stratification or therapeutic intervention remains to be confirmed through functional studies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our multi-omics integration revealed SCPEP1\n                      <jats:sup>+<\/jats:sup>\n                      basal cells as central oxidative stress responders and communication hubs in IPF. These findings provide insights into ROS-driven epithelial remodeling and highlight SCPEP1 as a potential contributor to disease-associated pathways that warrants further exploration for its diagnostic or therapeutic relevance.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1676086","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T05:12:39Z","timestamp":1765170759000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["SCPEP1+ basal cells are associated with the remodeling of oxidative stress signaling networks in idiopathic pulmonary fibrosis"],"prefix":"10.3389","volume":"16","author":[{"given":"Xiang","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenghao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simiao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meifeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengyu","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yupeng","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaying","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linyou","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1186\/s12967-025-06514-2","article-title":"et al: Pulmonary fibrosis: from mechanisms to therapies","volume":"23","author":"Jiang","year":"2025","journal-title":"J Trans Med"},{"key":"B2","doi-asserted-by":"publisher","first-page":"e744","DOI":"10.1002\/mco2.744","article-title":"Pulmonary fibrosis: pathogenesis and therapeutic strategies","volume":"5","author":"Wang","year":"2024","journal-title":"MedComm"},{"key":"B3","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1183\/09031936.00185114","article-title":"Global incidence and mortality of idiopathic pulmonary fibrosis: a systematic review","volume":"46","author":"Hutchinson","year":"2015","journal-title":"Eur Respir J"},{"key":"B4","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1186\/s12931-021-01791-z","article-title":"Global incidence and prevalence of idiopathic pulmonary fibrosis","volume":"22","author":"Maher","year":"2021","journal-title":"Respir Res"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2025.1578480","article-title":"Global, regional, and national burden of interstitial lung diseases and pulmonary sarcoidosis from 2000 to 2021: a systematic analysis of incidence, mortality, and disability-adjusted life years","volume":"13","author":"Zhou","year":"2025","journal-title":"Frontiers in Public Health."},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmed.2014.03.015","article-title":"The burden of idiopathic pulmonary fibrosis: An unmet public health need","volume":"108","author":"Lee","year":"2014","journal-title":"Respir Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.4103\/atm.atm_206_22","article-title":"Nintedanib and pirfenidone for idiopathic pulmonary fibrosis in King Abdulaziz Medical City, Riyadh: Real-life data","volume":"18","author":"Khan","year":"2023","journal-title":"Ann Thorac Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/life15010106","article-title":"Gender differences are a leading factor in 5-year survival of patients with idiopathic pulmonary fibrosis over antifibrotic therapy reduction","volume":"15","author":"Tondo","year":"2025","journal-title":"Life (Basel Switzerland)"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.pulmoe.2018.06.003","article-title":"Pirfenidone and Nintedanib in idiopathic pulmonary fibrosis: Real-life experience in an Italian referral centre","volume":"25","author":"Bargagli","year":"2019","journal-title":"Pulmonology"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2414108","article-title":"Nerandomilast in patients with idiopathic pulmonary fibrosis","volume":"392","author":"Richeldi","year":"2025","journal-title":"New England Journal of Medicine."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202401-0116OC","article-title":"Zinpentraxin alfa for idiopathic pulmonary fibrosis: the randomized phase III STARSCAPE trial","volume":"209","author":"Richeldi","year":"2024","journal-title":"Am J Respir Crit Care Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2007.1901","article-title":"Oxidative stress and antioxidants in the pathogenesis of pulmonary fibrosis: a potential role for Nrf2","volume":"10","author":"Walters","year":"2008","journal-title":"Antioxid Redox Signal"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmed.2009.04.014","article-title":"Oxidative stress in the pathogenesis of diffuse lung diseases: A review","volume":"103","author":"Bargagli","year":"2009","journal-title":"Respir Med"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1225578","DOI":"10.1155\/2022\/1225578","article-title":"ROS: basic concepts, sources, cellular signaling, and its implications in aging pathways","volume":"2022","author":"de Almeida","year":"2022","journal-title":"Oxid Med Cell Longevity"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2014.03.034","article-title":"ROS function in redox signaling and oxidative stress","volume":"24","author":"Schieber","year":"2014","journal-title":"Curr Biol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.794997","article-title":"Targeting oxidative stress as a therapeutic approach for idiopathic pulmonary fibrosis","volume":"12","author":"Estornut","year":"2022","journal-title":"Frontiers in Pharmacology."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2014.100","article-title":"Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-\u03b21 and TGF-\u03b22-dependent pathway","volume":"94","author":"Montorfano","year":"2014","journal-title":"Lab Invest"},{"key":"B18","doi-asserted-by":"publisher","first-page":"9932442","DOI":"10.1155\/2021\/9932442","article-title":"The role of interaction between mitochondria and the extracellular matrix in the development of idiopathic pulmonary fibrosis","volume":"2021","author":"Siekacz","year":"2021","journal-title":"Oxid Med Cell Longevity"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e34592","article-title":"Global research status and trends of interactions between Traditional Chinese medicine and pulmonary fibrosis: A new dawn in treatment","volume":"10","author":"Wei","year":"2024","journal-title":"Heliyon"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3390\/cells9081751","article-title":"Biological and medical importance of cellular heterogeneity deciphered by single-cell RNA sequencing","volume":"9","author":"Gupta","year":"2020","journal-title":"Cells"},{"key":"B21","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1007\/s12016-024-09001-6","article-title":"Single-cell sequencing: high-resolution analysis of cellular heterogeneity in autoimmune diseases","volume":"66","author":"Tang","year":"2024","journal-title":"Clin Rev Allergy Immunol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1126\/science.aaf2403","article-title":"Visualization and analysis of gene expression in tissue sections by spatial transcriptomics","volume":"353","author":"St\u00e5hl","year":"2016","journal-title":"Sci (New York NY)"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.7150\/thno.95908","article-title":"Spatial transcriptomics: A powerful tool in disease understanding and drug discovery","volume":"14","author":"Cao","year":"2024","journal-title":"Theranostics"},{"key":"B24","doi-asserted-by":"publisher","first-page":"100034","DOI":"10.1016\/j.neumar.2024.100034","article-title":"The role of machine learning in discovering biomarkers and predicting treatment strategies for neurodegenerative diseases: A narrative review","volume":"2","author":"Aborode","year":"2025","journal-title":"NeuroMarkers"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1725\u20131736","DOI":"10.1101\/2023.12.21.572330","article-title":"Translational mapping of spatially resolved transcriptomes in human and mouse pulmonary fibrosis","volume":"56","author":"Franz\u00e9n","year":"2023"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.02441-2018","article-title":"Proliferating SPP1\/MERTK-expressing macrophages in idiopathic pulmonary fibrosis","volume":"54","author":"Morse","year":"2019","journal-title":"Eur Respir J"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13969","article-title":"Transcriptional changes of the aging lung","volume":"22","author":"Jia","year":"2023","journal-title":"Aging Cell"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0090-y","article-title":"Reducing protein oxidation reverses lung fibrosis","volume":"24","author":"Anathy","year":"2018","journal-title":"Nat Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2012-202943","article-title":"Expression of cilium-associated genes defines novel molecular subtypes of idiopathic pulmonary fibrosis","volume":"68","author":"Yang","year":"2013","journal-title":"Thorax"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202001-0134OC","article-title":"Chronic hypersensitivity pneumonitis, an interstitial lung disease with distinct molecular signatures","volume":"202","author":"Furusawa","year":"2020","journal-title":"Am J Respir Crit Care Med"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1183\/23120541.00191-2022","article-title":"Matrix metalloproteinase-7 is increased in lung bases but not apices in idiopathic pulmonary fibrosis","volume":"8","author":"Jaffar","year":"2022","journal-title":"ERJ Open Res"},{"key":"B32","doi-asserted-by":"publisher","first-page":"140793","DOI":"10.1016\/j.ijbiomac.2025.140793","article-title":"Integration of single-cell and bulk RNA sequencing data using machine learning identifies oxidative stress-related genes LUM and PCOLCE2 as potential biomarkers for heart failure","volume":"300","author":"Li","year":"2025","journal-title":"Int J Biol macromolecules"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2018.00440","article-title":"Chemical proteomic analysis of serine hydrolase activity in niemann-pick type C mouse brain","volume":"12","author":"van Rooden","year":"2018","journal-title":"Frontiers in Neuroscience."},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0172854","article-title":"Mice, double deficient in lysosomal serine carboxypeptidases Scpep1 and Cathepsin A develop the hyperproliferative vesicular corneal dystrophy and hypertrophic skin thickenings","volume":"12","author":"Pan","year":"2017","journal-title":"PloS One"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1780","DOI":"10.1016\/j.chembiol.2021.06.003","article-title":"Combined morphological and proteome profiling reveals target-independent impairment of cholesterol homeostasis","volume":"28","author":"Schneidewind","year":"2021","journal-title":"Cell Chem Biol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1038\/s41467-025-56501-w","article-title":"Cloned airway basal progenitor cells to repair fibrotic lung through re-epithelialization","volume":"16","author":"Zhao","year":"2025","journal-title":"Nat Commun"},{"key":"B37","doi-asserted-by":"publisher","first-page":"5637","DOI":"10.1038\/s41467-022-33193-0","article-title":"Airway basal cells show a dedifferentiated KRT17highPhenotype and promote fibrosis in idiopathic pulmonary fibrosis","volume":"13","author":"Jaeger","year":"2022","journal-title":"Nat Commun"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3390\/cells11061050","article-title":"Emerging roles of airway epithelial cells in idiopathic pulmonary fibrosis","volume":"11","author":"Chakraborty","year":"2022","journal-title":"Cells"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.006031","article-title":"Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodeling","volume":"3","author":"Rock","year":"2010","journal-title":"Dis Models Mech"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2013.03.001","article-title":"Fibrosis of two: Epithelial cell-fibroblast interactions in pulmonary fibrosis","volume":"1832","author":"Sakai","year":"2013","journal-title":"Biochim Biophys Acta"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.199869","article-title":"Functional characterization of a putative serine carboxypeptidase in vascular smooth muscle cells","volume":"105","author":"Lee","year":"2009","journal-title":"Circ Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2024-0372TR","article-title":"From epithelium to therapy: transitional cells in lung fibrosis","volume":"72","author":"Shin","year":"2025","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3389\/falgy.2021.787128","article-title":"Airway basal cells, protectors of epithelial walls in health and respiratory diseases","volume":"2","author":"Ruysseveldt","year":"2021","journal-title":"Front Allergy"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-041520-092904","article-title":"Epithelial stem and progenitor cells in lung repair and regeneration","volume":"83","author":"Alysandratos","year":"2021","journal-title":"Annu Rev Physiol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"114653","DOI":"10.1016\/j.intimp.2025.114653","article-title":"Idiopathic pulmonary fibrosis microenvironment: Novel mechanisms and research directions","volume":"155","author":"Gao","year":"2025","journal-title":"Int Immunopharmacol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241512490","article-title":"Oxidative stress and lung fibrosis: towards an adverse outcome pathway","volume":"24","author":"Makena","year":"2023","journal-title":"Int J Mol Sci"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1676086\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T05:12:40Z","timestamp":1765170760000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1676086\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,8]]},"references-count":46,"alternative-id":["10.3389\/fimmu.2025.1676086"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1676086","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,8]]},"article-number":"1676086"}}