{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T00:57:44Z","timestamp":1794013064965,"version":"4.8.0"},"reference-count":26,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2023A1515111103"],"award-info":[{"award-number":["2023A1515111103"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Affiliated Hospital of Guangdong Medical University High level Talent Research Launch Project","award":["GCC2024004"],"award-info":[{"award-number":["GCC2024004"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Ankylosing spondylitis (AS), a chronic inflammatory disorder affecting axial joints, is frequently complicated by uveitis. However, the molecular mechanisms linking AS to secondary uveitis remain poorly understood.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>We integrated transcriptomic datasets from AS (GSE73754) and uveitis (GSE194060) cohorts to identify shared molecular pathways. Differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning (LASSO, SVM-RFE, random forest) were combined to prioritize biomarkers. Molecular docking was performed to evaluate drug-target interactions using Vina scores (\u2264\u22127 kcal\/mol threshold).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Cross-disease analysis revealed 697 overlapping dysregulated genes (481 upregulated, 216 downregulated), enriched in GTPase signaling and immune pathways. WGCNA identified disease-specific co-expression modules (AS: brown\/tan modules, <jats:italic><jats:italic>r<\/jats:italic><\/jats:italic>\u2009=\u20090.39\/0.35; uveitis: brown module, <jats:italic><jats:italic>r<\/jats:italic><\/jats:italic>\u2009=\u20090.49). Machine learning nominated HLX and SLC25A20 as core biomarkers, demonstrating robust diagnostic accuracy in discovery (AS AUC: 0.688\/0.700; uveitis AUC: 0.867\/0.838) and validation cohorts (AS AUC: 0.653\/0.667; uveitis AUC: 0.662\/0.736). Immune profiling linked HLX to neutrophil infiltration (<jats:italic><jats:italic>r<\/jats:italic><\/jats:italic>\u2009=\u20090.55, <jats:italic><jats:italic>p<\/jats:italic><\/jats:italic>\u2009&lt;\u20090.01) and SLC25A20 to T helper cell regulation (<jats:italic><jats:italic>r<\/jats:italic><\/jats:italic>\u2009=\u20090.36, p\u2009&lt;\u20090.01). Molecular docking identified high-affinity ligands for SLC25A20, including amiodarone (\u22128.0 kcal\/mol) and estradiol (\u22127.7 kcal\/mol), with folic acid showing dual binding potential (HLX: \u22127.5 kcal\/mol; SLC25A20: \u22128.2 kcal\/mol).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>HLX and SLC25A20 emerge as immunologic regulators bridging AS and uveitis pathogenesis. These findings provide actionable targets for precision diagnostics and therapeutic development in AS-associated uveitis.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0332049","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T17:33:02Z","timestamp":1757525582000},"page":"e0332049","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["HLX and SLC25A20: Immunologic regulators bridging ankylosing spondylitis and uveitis via multi-omics integration and machine learning"],"prefix":"10.1371","volume":"20","author":[{"given":"Weiming","family":"Cai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huayan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongbo","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4617-8221","authenticated-orcid":true,"given":"Tangming","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"issue":"26","key":"pone.0332049.ref001","doi-asserted-by":"crossref","first-page":"2563","DOI":"10.1056\/NEJMra1406182","article-title":"Ankylosing Spondylitis and Axial Spondyloarthritis","volume":"374","author":"JD Taurog","year":"2016","journal-title":"N Engl J Med"},{"issue":"6","key":"pone.0332049.ref002","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/nrrheum.2017.56","article-title":"Pathogenesis of ankylosing spondylitis - recent advances and future directions","volume":"13","author":"V Ranganathan","year":"2017","journal-title":"Nat Rev Rheumatol"},{"issue":"9","key":"pone.0332049.ref003","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s11926-015-0536-x","article-title":"Acute Anterior Uveitis and Spondyloarthritis: More Than Meets the Eye","volume":"17","author":"MA Khan","year":"2015","journal-title":"Curr Rheumatol Rep"},{"issue":"1","key":"pone.0332049.ref004","doi-asserted-by":"crossref","first-page":"14779","DOI":"10.1038\/s41598-023-41971-z","article-title":"The effect of uveitis and undiagnosed spondyloarthritis: a systematic review and meta-analysis","volume":"13","author":"S-C Lee","year":"2023","journal-title":"Sci Rep"},{"issue":"11","key":"pone.0332049.ref005","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1136\/ard-2024-225661","article-title":"HLA-B27 and the role of specific T cell receptors in the pathogenesis of spondyloarthritis","volume":"83","author":"J Braun","year":"2024","journal-title":"Ann Rheum Dis"},{"issue":"5","key":"pone.0332049.ref006","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1007\/s11926-017-0654-8","article-title":"Ankylosing Spondylitis: HLA-B*27-Positive Versus HLA-B*27-Negative Disease","volume":"19","author":"N Akko\u00e7","year":"2017","journal-title":"Curr Rheumatol Rep"},{"issue":"11","key":"pone.0332049.ref007","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1136\/ard.2011.152975","article-title":"HLA-B27 positive patients differ from HLA-B27 negative patients in clinical presentation and imaging: results from the DESIR cohort of patients with recent onset axial spondyloarthritis","volume":"70","author":"HY Chung","year":"2011","journal-title":"Ann Rheum Dis"},{"issue":"2","key":"pone.0332049.ref008","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1136\/ard-2022-223146","article-title":"Card9\/neutrophil signalling axis promotes IL-17A-mediated ankylosing spondylitis","volume":"83","author":"HL Rosenzweig","year":"2024","journal-title":"Ann Rheum Dis"},{"issue":"12","key":"pone.0332049.ref009","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/s41584-019-0294-7","article-title":"The IL-23-IL-17 pathway as a therapeutic target in axial spondyloarthritis","volume":"15","author":"J Sieper","year":"2019","journal-title":"Nat Rev Rheumatol"},{"key":"pone.0332049.ref010","doi-asserted-by":"crossref","first-page":"100866","DOI":"10.1016\/j.preteyeres.2020.100866","article-title":"Activation of the interleukin-23\/interleukin-17 signalling pathway in autoinflammatory and autoimmune uveitis","volume":"80","author":"Z Zhong","year":"2021","journal-title":"Prog Retin Eye Res"},{"issue":"7941","key":"pone.0332049.ref011","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/s41586-022-05501-7","article-title":"Autoimmunity-associated T cell receptors recognize HLA-B*27-bound peptides","volume":"612","author":"X Yang","year":"2022","journal-title":"Nature"},{"issue":"3","key":"pone.0332049.ref012","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1002\/art.41129","article-title":"Altered Cytotoxicity Profile of CD8+ T Cells in Ankylosing Spondylitis","volume":"72","author":"E Gracey","year":"2020","journal-title":"Arthritis Rheumatol"},{"issue":"11","key":"pone.0332049.ref013","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1136\/ard-2024-226018","article-title":"Altered CD8+ T cell subpopulation in the bone marrow microenvironment of cynomolgus monkeys with spontaneous ankylosing spondylitis","volume":"83","author":"T Guan","year":"2024","journal-title":"Ann Rheum Dis"},{"key":"pone.0332049.ref014","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.jconrel.2024.06.047","article-title":"Polyvinylpyrrolidone-curcumin nanoparticles with immune regulatory and metabolism regulatory effects for the treatment of experimental autoimmune uveitis","volume":"372","author":"F Cao","year":"2024","journal-title":"J Control Release"},{"issue":"13","key":"pone.0332049.ref015","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1167\/iovs.64.13.39","article-title":"Local Myeloid-Derived Suppressor Cells Impair Progression of Experimental Autoimmune Uveitis by Alleviating Oxidative Stress and Inflammation","volume":"64","author":"J-Y Lee","year":"2023","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"pone.0332049.ref016","doi-asserted-by":"crossref","first-page":"102920","DOI":"10.1016\/j.jaut.2022.102920","article-title":"Transcriptomic profiling of iris tissue highlights LCK signaling and T cell-mediated immunity in Behcet\u2019s uveitis","volume":"133","author":"Y Deng","year":"2022","journal-title":"J Autoimmun"},{"issue":"11","key":"pone.0332049.ref017","article-title":"Comprehensive single-cell profiling of monocytes in HLA-B27-positive ankylosing spondylitis with acute anterior uveitis","volume":"5","author":"H Li","year":"2024","journal-title":"MedComm (2020)"},{"key":"pone.0332049.ref018","doi-asserted-by":"crossref","first-page":"102597","DOI":"10.1016\/j.jaut.2021.102597","article-title":"TLR expression profiles are a function of disease status in rheumatoid arthritis and experimental arthritis","volume":"118","author":"FIL Clanchy","year":"2021","journal-title":"J Autoimmun"},{"issue":"8","key":"pone.0332049.ref019","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1111\/j.1442-9071.2012.02797.x","article-title":"Recent advances in Toll-like receptors and anterior uveitis","volume":"40","author":"JH Chang","year":"2012","journal-title":"Clin Exp Ophthalmol"},{"issue":"2","key":"pone.0332049.ref020","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1189\/jlb.0207111","article-title":"Induction of a distinct CD8 Tnc17 subset by transforming growth factor-beta and interleukin-6","volume":"82","author":"S-J Liu","year":"2007","journal-title":"J Leukoc Biol"},{"key":"pone.0332049.ref021","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jaut.2014.05.006","article-title":"MBD2 regulates TH17 differentiation and experimental autoimmune encephalomyelitis by controlling the homeostasis of T-bet\/Hlx axis","volume":"53","author":"J Zhong","year":"2014","journal-title":"J Autoimmun"},{"issue":"4","key":"pone.0332049.ref022","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/s41419-021-03648-1","article-title":"Down-regulation of SLC25A20 promotes hepatocellular carcinoma growth and metastasis through suppression of fatty-acid oxidation","volume":"12","author":"P Yuan","year":"2021","journal-title":"Cell Death Dis"},{"issue":"12","key":"pone.0332049.ref023","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1021\/acscentsci.7b00420","article-title":"Chemical Proteomics Identifies SLC25A20 as a Functional Target of the Ingenol Class of Actinic Keratosis Drugs","volume":"3","author":"CG Parker","year":"2017","journal-title":"ACS Cent Sci"},{"key":"pone.0332049.ref024","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1016\/j.ijbiomac.2022.09.135","article-title":"Proline\/Glycine residues of the PG-levels guide conformational changes along the transport cycle in the mitochondrial carnitine\/acylcarnitine carrier (SLC25A20)","volume":"221","author":"N Giangregorio","year":"2022","journal-title":"Int J Biol Macromol"},{"key":"pone.0332049.ref025","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1471-2105-14-7","article-title":"GSVA: gene set variation analysis for microarray and RNA-seq data","volume":"14","author":"S H\u00e4nzelmann","year":"2013","journal-title":"BMC Bioinformatics"},{"issue":"4","key":"pone.0332049.ref026","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/j.immuni.2013.10.003","article-title":"Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer","volume":"39","author":"G Bindea","year":"2013","journal-title":"Immunity"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0332049","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T17:33:07Z","timestamp":1757525587000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0332049"}},"subtitle":[],"editor":[{"given":"Mark","family":"Hwang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,9,10]]},"references-count":26,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9,10]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0332049","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,10]]}}}