{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:40:39Z","timestamp":1792172439970,"version":"4.4.0"},"reference-count":60,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T00:00:00Z","timestamp":1747872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AbbVie"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Proteomes"],"abstract":"<jats:p>Understanding the heterogeneity of Rheumatoid Arthritis (RA) and identifying therapeutic targets remain challenging using traditional bulk transcriptomics alone, as it lacks the spatial and protein-level resolution needed to fully capture disease and tissue complexities. In this study, we applied Laser Capture Microdissection (LCM) coupled with mass spectrometry-based proteomics to analyze histopathological niches of the RA synovium, enabling the identification of protein expression profiles of the diseased synovial lining and sublining microenvironments compared to their healthy counterparts. In this respect, key pathogenetic RA proteins like membrane proteins (TYROBP, AOC3, SLC16A3, TCIRG1, and NCEH1), and extracellular matrix (ECM) proteins (PLOD2, OGN, and LUM) showed different expression patterns in diseased synovium compartments. To enhance our understanding of cellular dynamics within the dissected regions, we further integrated the proteomic dataset with single-cell RNA sequencing (scRNA-seq), and deduced cell type enrichment, including T cells, fibroblasts, NK cells, myeloid cells, B cells, and synovial endothelial cells. By combining high-resolution spatial proteomics and transcriptomic analyses, we provide novel insights into the molecular mechanisms driving RA, and highlight potential protein targets for therapeutic intervention. This integrative approach offers a more comprehensive view of RA synovial pathology, and mitigates the limitations of traditional bulk transcriptomics in target discovery.<\/jats:p>","DOI":"10.3390\/proteomes13020017","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T07:04:28Z","timestamp":1747897468000},"page":"17","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Integrative Spatial Proteomics and Single-Cell RNA Sequencing Unveil Molecular Complexity in Rheumatoid Arthritis for Novel Therapeutic Targeting"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5267-6083","authenticated-orcid":false,"given":"Xue","family":"Wang","sequence":"first","affiliation":[{"name":"AbbVie, South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Wang","sequence":"additional","affiliation":[{"name":"AbbVie Bioresearch Center, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Archana S.","family":"Iyer","sequence":"additional","affiliation":[{"name":"AbbVie Bioresearch Center, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Knight","sequence":"additional","affiliation":[{"name":"AbbVie Bioresearch Center, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lori J.","family":"Duggan","sequence":"additional","affiliation":[{"name":"AbbVie Bioresearch Center, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingli","family":"Yang","sequence":"additional","affiliation":[{"name":"AbbVie Bioresearch Center, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Jin","sequence":"additional","affiliation":[{"name":"AbbVie Bioresearch Center, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoliang","family":"Cui","sequence":"additional","affiliation":[{"name":"AbbVie Bioresearch Center, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yupeng","family":"He","sequence":"additional","affiliation":[{"name":"AbbVie, North Chicago, IL 60064, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Schejbal","sequence":"additional","affiliation":[{"name":"AbbVie Bioresearch Center, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy A.","family":"Phillips","sequence":"additional","affiliation":[{"name":"AbbVie Bioresearch Center, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bohdan P.","family":"Harvey","sequence":"additional","affiliation":[{"name":"AbbVie, Cambridge, MA 02139, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3642-2956","authenticated-orcid":false,"given":"S\u00edlvia","family":"Sis\u00f3","sequence":"additional","affiliation":[{"name":"AbbVie Bioresearch Center, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3754-5875","authenticated-orcid":false,"given":"Yu","family":"Tian","sequence":"additional","affiliation":[{"name":"AbbVie Bioresearch Center, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/s41586-023-06708-y","article-title":"Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes","volume":"623","author":"Zhang","year":"2023","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2130","DOI":"10.1002\/art.42642","article-title":"Synovial Tissue Heterogeneity in Japanese Patients with Rheumatoid Arthritis Elucidated Using a Cell-Type Deconvolution Approach","volume":"75","author":"Nakajima","year":"2023","journal-title":"Arthritis Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"12973","DOI":"10.1021\/acs.analchem.4c00523","article-title":"Coupling Microdroplet-Based Sample Preparation, Multiplexed Isobaric Labeling, and Nanoflow Peptide Fractionation for Deep Proteome Profiling of the Tissue Microenvironment","volume":"96","author":"Velickovic","year":"2024","journal-title":"Anal. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1038\/s41587-022-01302-5","article-title":"Deep Visual Proteomics defines single-cell identity and heterogeneity","volume":"40","author":"Mund","year":"2022","journal-title":"Nat. Biotechnol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3777","DOI":"10.1039\/D1AN00472G","article-title":"Spatial proteomics for understanding the tissue microenvironment","volume":"146","author":"Mao","year":"2021","journal-title":"Analyst"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"9378","DOI":"10.1038\/s41467-024-53683-7","article-title":"Spatial proteomics of single cells and organelles on tissue slides using filter-aided expansion proteomics","volume":"15","author":"Dong","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"110955","DOI":"10.1016\/j.celrep.2022.110955","article-title":"Spatial region-resolved proteome map reveals mechanism of COVID-19-associated heart injury","volume":"39","author":"Leng","year":"2022","journal-title":"Cell Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1007\/s00011-023-01767-3","article-title":"Spatial proteomics landscape and immune signature analysis of renal sample of lupus nephritis based on laser-captured microsection","volume":"72","author":"Zheng","year":"2023","journal-title":"Inflamm. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1080\/01478885.2024.2391683","article-title":"A best practices framework for spatial biology studies in drug discovery and development: Enabling successful cohort studies using digital spatial profiling","volume":"48","author":"Krull","year":"2024","journal-title":"J. Histotechnol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1021\/acs.analchem.2c04220","article-title":"MALDI-IHC-Guided In-Depth Spatial Proteomics: Targeted and Untargeted MSI Combined","volume":"95","author":"Claes","year":"2023","journal-title":"Anal. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.1016\/j.molcel.2022.05.022","article-title":"Unbiased spatial proteomics with single-cell resolution in tissues","volume":"82","author":"Mund","year":"2022","journal-title":"Mol. Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41592-019-0638-x","article-title":"DIA-NN: Neural networks and interference correction enable deep proteome coverage in high throughput","volume":"17","author":"Demichev","year":"2020","journal-title":"Nat. Methods"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1093\/bioinformatics\/btr597","article-title":"MissForest--non-parametric missing value imputation for mixed-type data","volume":"28","author":"Stekhoven","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Jin, L., Bi, Y., Hu, C., Qu, J., Shen, S., Wang, X., and Tian, Y. (2021). A comparative study of evaluating missing value imputation methods in label-free proteomics. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-81279-4"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"W415","DOI":"10.1093\/nar\/gkae456","article-title":"WebGestalt 2024: Faster gene set analysis and new support for metabolomics and multi-omics","volume":"52","author":"Elizarraras","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"W199","DOI":"10.1093\/nar\/gkz401","article-title":"WebGestalt 2019: Gene set analysis toolkit with revamped UIs and APIs","volume":"47","author":"Liao","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/s41587-019-0392-8","article-title":"Integrating microarray-based spatial transcriptomics and single-cell RNA-seq reveals tissue architecture in pancreatic ductal adenocarcinomas","volume":"38","author":"Moncada","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Wang, F., Jin, L., Wang, X., Cui, B., Yang, Y., Duggan, L., Schwartz Sterman, A., Lloyd, S.M., Hazelwood, L.A., and Chaudhary, N. (2025). Novel Integration of Spatial and Single-Cell Omics Data Sets Enables Deeper Insights into IPF Pathogenesis. Proteomes, 13.","DOI":"10.3390\/proteomes13010003"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1097\/BOR.0b013e32835fd8eb","article-title":"New learnings on the pathophysiology of RA from synovial biopsies","volume":"25","author":"Pitzalis","year":"2013","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1002\/art.41184","article-title":"B Cell Synovitis and Clinical Phenotypes in Rheumatoid Arthritis: Relationship to Disease Stages and Drug Exposure","volume":"72","author":"Rivellese","year":"2020","journal-title":"Arthritis Rheumatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","article-title":"Causal analysis approaches in Ingenuity Pathway Analysis","volume":"30","author":"Kramer","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hynes, R.O., and Naba, A. (2012). Overview of the matrisome--an inventory of extracellular matrix constituents and functions. Cold Spring Harb. Perspect. Biol., 4.","DOI":"10.1101\/cshperspect.a004903"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1084\/jem.20090516","article-title":"Myeloid DAP12-associating lectin (MDL)-1 regulates synovial inflammation and bone erosion associated with autoimmune arthritis","volume":"207","author":"Bigler","year":"2010","journal-title":"J. Exp. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1024\/0301-1526\/a001031","article-title":"Vascular adhesion protein-1 (VAP-1) in vascular inflammatory diseases","volume":"51","author":"Danielli","year":"2022","journal-title":"Vasa"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Pucino, V., Nefla, M., Gauthier, V., Alsaleh, G., Clayton, S.A., Marshall, J., Filer, A., Clark, A.R., Raza, K., and Buckley, C.D. (2023). Differential effect of lactate on synovial fibroblast and macrophage effector functions. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1183825"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1111\/j.1365-2249.2006.03044.x","article-title":"Antibody targeting of TIRC7 results in significant therapeutic effects on collagen-induced arthritis in mice","volume":"144","author":"Utku","year":"2006","journal-title":"Clin. Exp. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Jiang, H., Chen, W., Zhu, G., Zhang, L., Tucker, B., Hao, L., Feng, S., Ci, H., Ma, J., and Wang, L. (2013). RNAi-mediated silencing of Atp6i and Atp6i haploinsufficiency prevents both bone loss and inflammation in a mouse model of periodontal disease. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0058599"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1186\/s12967-023-04758-4","article-title":"Multiplex immunohistochemistry defines two cholesterol metabolism patterns predicting immunotherapeutic outcomes in gastric cancer","volume":"21","author":"Tang","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"18","DOI":"10.14573\/altex.1804161","article-title":"A three-dimensional model to study human synovial pathology","volume":"36","author":"Broeren","year":"2019","journal-title":"ALTEX"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5001","DOI":"10.2147\/JIR.S431076","article-title":"The m6A\/m1A\/m5C-Related Methylation Modification Patterns and Immune Landscapes in Rheumatoid Arthritis and Osteoarthritis Revealed by Microarray and Single-Cell Transcriptome","volume":"16","author":"Zheng","year":"2023","journal-title":"J. Inflamm. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/1559-0275-10-11","article-title":"A multilectin affinity approach for comparative glycoprotein profiling of rheumatoid arthritis and spondyloarthropathy","volume":"10","author":"Bhattacharjee","year":"2013","journal-title":"Clin. Proteomics"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1002\/1529-0131(199808)41:8<1356::AID-ART4>3.0.CO;2-X","article-title":"Use of a differential subtraction method to identify genes that characterize the phenotype of cultured rheumatoid arthritis synoviocytes","volume":"41","author":"Seki","year":"1998","journal-title":"Arthritis Rheum."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"665","DOI":"10.2522\/ptj.20100065","article-title":"Ex vivo soft-laser treatment inhibits the synovial expression of vimentin and alpha-enolase, potential autoantigens in rheumatoid arthritis","volume":"91","author":"Balint","year":"2011","journal-title":"Phys. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"368","DOI":"10.3109\/03009741003742771","article-title":"Small molecules regulating apoptosis in the synovium in rheumatoid arthritis","volume":"39","author":"Dubikov","year":"2010","journal-title":"Scand. J. Rheumatol."},{"key":"ref_36","first-page":"10","article-title":"Reduced chemokine and matrix metalloproteinase expression in patients with rheumatoid arthritis achieving remission","volume":"30","author":"Katrib","year":"2003","journal-title":"J. Rheumatol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Fuentelsaz-Romero, S., Cuervo, A., Estrada-Capetillo, L., Celis, R., Garcia-Campos, R., Ramirez, J., Sastre, S., Samaniego, R., Puig-Kroger, A., and Canete, J.D. (2020). GM-CSF Expression and Macrophage Polarization in Joints of Undifferentiated Arthritis Patients Evolving to Rheumatoid Arthritis or Psoriatic Arthritis. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.613975"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3595","DOI":"10.1002\/art.27701","article-title":"CD248 and its cytoplasmic domain: A therapeutic target for arthritis","volume":"62","author":"Maia","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Wang, Z., Wang, J., Lan, T., Zhang, L., Yan, Z., Zhang, N., Xu, Y., and Tao, Q. (2023). Role and mechanism of fibroblast-activated protein-alpha expression on the surface of fibroblast-like synoviocytes in rheumatoid arthritis. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1135384"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1007\/s11307-023-01817-6","article-title":"Evaluation of F-FAPI-04 Imaging in Assessing the Therapeutic Response of Rheumatoid Arthritis","volume":"25","author":"Zhang","year":"2023","journal-title":"Mol. Imaging Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"R433","DOI":"10.1186\/ar1212","article-title":"Direct Toll-like receptor 2 mediated co-stimulation of T cells in the mouse system as a basis for chronic inflammatory joint disease","volume":"6","author":"Sobek","year":"2004","journal-title":"Arthritis Res. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3753","DOI":"10.1002\/art.24127","article-title":"Shift From Toll-like Receptor 2 (TLR-2) Toward TLR-4 Dependency in the Erosive Stage of Chronic Streptococcal Cell Wall Arthritis Coincident With TLR-4-Mediated Interleukin-17 Production","volume":"58","author":"Joosten","year":"2008","journal-title":"Arthritis Rheum."},{"key":"ref_43","first-page":"1313","article-title":"Tofacitinib inhibits CD4 T cell polarisation to Th1 during priming thereby leading to clinical impact in a model of experimental arthritis","volume":"40","author":"Bedaj","year":"2022","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e407","DOI":"10.1097\/RHU.0000000000001749","article-title":"The Risk of Infections Associated With JAK Inhibitors in Rheumatoid Arthritis: A Systematic Review and Network Meta-analysis","volume":"28","author":"Alves","year":"2022","journal-title":"J. Clin. Rheumatol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1002\/0470856734.ch5","article-title":"Anti-TNFalpha therapy of rheumatoid arthritis: What can we learn about chronic disease?","volume":"256","author":"Feldmann","year":"2004","journal-title":"Novartis Found. Symp."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"363","DOI":"10.2174\/1568010054022141","article-title":"Matrix metalloproteinase knockout studies and the potential use of matrix metalloproteinase inhibitors in the rheumatic diseases","volume":"4","author":"Milner","year":"2005","journal-title":"Curr. Drug Targets Inflamm. Allergy"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.bcp.2012.06.026","article-title":"N-O-Isopropyl sulfonamido-based hydroxamates: Kinetic characterisation of a series of MMP-12\/MMP-13 dual target inhibitors","volume":"84","author":"Santamaria","year":"2012","journal-title":"Biochem. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"de Seny, D., Baiwir, D., Bianchi, E., Cobraiville, G., Deroyer, C., Poulet, C., Malaise, O., Paulissen, G., Kaiser, M.J., and Hauzeur, J.P. (2021). New Proteins Contributing to Immune Cell Infiltration and Pannus Formation of Synovial Membrane from Arthritis Diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23010434"},{"key":"ref_49","first-page":"106","article-title":"[Activity of the prekallikrein-kallikrein system and characteristics of its regulation in various allergies]","volume":"32","author":"Nenasheva","year":"1986","journal-title":"Vopr. Med. Khim"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4746","DOI":"10.1021\/acs.jproteome.1c00399","article-title":"Quantitative Proteomic Analysis of Synovial Tissue Reveals That Upregulated OLFM4 Aggravates Inflammation in Rheumatoid Arthritis","volume":"20","author":"Ren","year":"2021","journal-title":"J. Proteome Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"40967","DOI":"10.1074\/jbc.M307380200","article-title":"Identification of PLOD2 as telopeptide lysyl hydroxylase, an important enzyme in fibrosis","volume":"278","author":"Zuurmond","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1988","DOI":"10.1074\/mcp.M800518-MCP200","article-title":"Equivalence of protein inventories obtained from formalin-fixed paraffin-embedded and frozen tissue in multidimensional liquid chromatography-tandem mass spectrometry shotgun proteomic analysis","volume":"8","author":"Sprung","year":"2009","journal-title":"Mol. Cell Proteom."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/978-1-0716-2831-7_9","article-title":"DIGE Saturation Labeling for Scarce Amounts of Protein from Formalin-Fixed Paraffin-Embedded (FFPE) Tissue","volume":"2596","author":"Dowling","year":"2023","journal-title":"Methods Mol. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1002\/pmic.201300311","article-title":"Applications of mass spectrometry for quantitative protein analysis in formalin-fixed paraffin-embedded tissues","volume":"14","author":"Steiner","year":"2014","journal-title":"Proteomics"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"6891","DOI":"10.1021\/acsomega.4c09289","article-title":"Overlap of Formalin-Fixed Paraffin-Embedded and Fresh-Frozen Matched Tissues for Proteomics and Phosphoproteomics","volume":"10","author":"Humphries","year":"2025","journal-title":"ACS Omega"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Obi, E.N., Tellock, D.A., Thomas, G.J., and Veenstra, T.D. (2023). Biomarker Analysis of Formalin-Fixed Paraffin-Embedded Clinical Tissues Using Proteomics. Biomolecules, 13.","DOI":"10.3390\/biom13010096"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Roberts, A.L., Mavlyutov, T.A., Perlmutter, T.E., Curry, S.M., Harris, S.L., Chauhan, A.K., and McDowell, C.M. (2020). Fibronectin extra domain A (FN-EDA) elevates intraocular pressure through Toll-like receptor 4 signaling. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-66756-6"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1083\/jcb.142.3.873","article-title":"The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-\u03b21","volume":"142","author":"Serini","year":"1998","journal-title":"J. Cell Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1083\/jcb.200212079","article-title":"Regulated splicing of the fibronectin EDA exon is essential for proper skin wound healing and normal lifespan","volume":"162","author":"Muro","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s42358-022-00247-2","article-title":"Fibronectin extra domain A as a drug delivery targeting epitope for rheumatoid arthritis","volume":"62","author":"Sun","year":"2022","journal-title":"Adv. Rheumatol."}],"container-title":["Proteomes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-7382\/13\/2\/17\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:38:20Z","timestamp":1760031500000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-7382\/13\/2\/17"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,22]]},"references-count":60,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["proteomes13020017"],"URL":"https:\/\/doi.org\/10.3390\/proteomes13020017","relation":{},"ISSN":["2227-7382"],"issn-type":[{"value":"2227-7382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,22]]}}}