{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T22:02:10Z","timestamp":1768255330709,"version":"3.49.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T00:00:00Z","timestamp":1757030400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2023J011199, 2024J011014, 2023Y9305, 2023Y9318"],"award-info":[{"award-number":["2023J011199, 2024J011014, 2023Y9305, 2023Y9318"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Sarcopenia associated with systemic sclerosis (SSc) significantly compromises patient prognosis and quality of life. However, reliable diagnostic biomarkers remain lacking. This study aimed to identify molecular markers for early detection using integrative computational approaches.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>An integrated analysis based on the Gene Expression Omnibus (GEO) database was performed. Crosstalk genes (CGs) were identified using least absolute shrinkage and selection operator (LASSO) regularization, ensemble decision trees, and support vector machine-based feature selection. Machine learning algorithms were employed to construct a predictive scoring model and to assess the diagnostic value of key biomarkers. Hub mRNAs were validated using quantitative polymerase chain reaction (qPCR). Immune cell infiltration profiles and functional correlations were also examined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Five key CGs\u2014NOX4, STC2, NEK6, IGSF10, and EMX2\u2014were identified as molecular links between SSc and sarcopenia. A predictive model incorporating NOX4 and NEK6 was developed, and a diagnostic threshold was established. PCR validation confirmed the differential expression of NOX4 and NEK6 in both SSc and SSc-associated sarcopenia, demonstrating high predictive accuracy. Furthermore, the combined NOX4-NEK6 model exhibited a superior area under the curve (AUC) compared to either gene alone. Immune infiltration analysis revealed significant correlations between CGs and multiple immune cell populations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study proposes NOX4 and NEK6 as novel biomarkers, offering a non-invasive strategy for the early detection of SSc-associated sarcopenia. This study also reveals a shared immune-dysregulation node linking SSc and sarcopenia, positions these crosstalk genes as multi-disease prevention targets, and paves the way for personalized immunotherapy and rapid bench-to-bedside translation.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1642806","type":"journal-article","created":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T05:22:04Z","timestamp":1757049724000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of crosstalk genes and diagnostic biomarkers in systemic sclerosis associated sarcopenia through integrative analysis and machine learning"],"prefix":"10.3389","volume":"16","author":[{"given":"Yanfang","family":"Wu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunfeng","family":"Dai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fei","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiping","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuyao","family":"Pan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juanjuan","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianwen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"He","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhihan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junping","family":"Wen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)31138-9","article-title":"Sarcopenia","volume":"393","author":"Cruz-Jentoft","year":"2019","journal-title":"Lancet (London England)"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2023.101883","article-title":"An elusive consensus definition of sarcopenia impedes research and clinical treatment: A narrative review","volume":"86","author":"Coletta","year":"2023","journal-title":"Ageing Res Rev"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2023.155533","article-title":"Epidemiology of sarcopenia: Prevalence, risk factors, and consequences","volume":"144","author":"Yuan","year":"2023","journal-title":"Metabolism: Clin Exp"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1586\/egh.13.22","article-title":"Systemic sclerosis and the gut","volume":"7","author":"Butt","year":"2013","journal-title":"Expert Rev Gastroenterol Hepatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-017-3932-y","article-title":"Malnutrition and sarcopenia in a large cohort of patients with systemic sclerosis","volume":"37","author":"Caimmi","year":"2018","journal-title":"Clin Rheumatol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.nut.2018.03.046","article-title":"Prevalence of sarcopenia in systemic sclerosis: assessing body composition and functional disability in patients with systemic sclerosis","author":"Siegert","year":"2018","journal-title":"Nutr (Burbank Los Angeles County Calif.)"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-019-04401-w","article-title":"Sarcopenia in systemic sclerosis: the impact of nutritional, clinical, and laboratory features","volume":"39","author":"Corallo","year":"2019","journal-title":"Rheumatol Int"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.13221","article-title":"Sarcopenia and cardiovascular diseases: A systematic review and meta-analysis","volume":"14","author":"Zuo","year":"2023","journal-title":"J cachexia sarcopenia Muscle"},{"key":"B9","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.amjms.2024.07.025","article-title":"Clinical outcomes and associated factors with mortality in systemic sclerosis patients with sarcopenia","volume":"369","author":"Hongkanjanapong","year":"2025","journal-title":"Am J Med Sci"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.21037\/qims.2020.03.05","article-title":"Muscle mass assessment in renal disease: the role of imaging techniques","volume":"10","author":"Sabatino","year":"2020","journal-title":"Quantitative Imaging Med Surg"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1177\/11795514241274691","article-title":"Agreement between bioelectrical impedance analysis and dual-energy X-ray absorptiometry to estimate fat mass in hispanic adults with type 2 diabetes mellitus: A cross-sectional study","volume":"17","author":"Castillo Castro","year":"2024","journal-title":"Clin Med Insights Endocrinol Diabetes"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.archger.2023.105059","article-title":"Are sit-to-stand and isometric handgrip tests comparable assessment tools to identify dynapenia in sarcopenic people","volume":"114","author":"Coelho-J\u00fanior","year":"2023","journal-title":"Arch gerontology geriatrics"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1093\/ptj\/pzab299","article-title":"Sex- and age-specific centile curves and downloadable calculator for clinical muscle strength tests to identify probable sarcopenia","volume":"102","author":"Warden","year":"2022","journal-title":"Phys Ther"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2020.101200","article-title":"Sarcopenia - Molecular mechanisms and open questions","volume":"65","author":"Wiedmer","year":"2021","journal-title":"Ageing Res Rev"},{"key":"B15","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1186\/s12967-025-06575-3","article-title":"Biomarkers for sarcopenia, muscle mass, muscle strength, and physical performance: an umbrella review","volume":"23","author":"Liu","year":"2025","journal-title":"J Trans Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3390\/cells12192422","article-title":"Current nutritional and pharmacological approaches for attenuating sarcopenia","volume":"12","author":"Sakuma","year":"2023","journal-title":"Cells"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3390\/clinpract14040117","article-title":"Dietary protein and physical exercise for the treatment of sarcopenia","volume":"14","author":"Nasso","year":"2024","journal-title":"Clinics Pract"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.2147\/CIA.S455736","article-title":"Non-pharmacological strategies for managing sarcopenia in chronic diseases","volume":"19","author":"Hu","year":"2024","journal-title":"Clin Interventions Aging"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkl887","article-title":"NCBI GEO: mining tens of millions of expression profiles\u2013database and tools update","volume":"35","author":"Barrett","year":"2007","journal-title":"Nucleic Acids Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2021-221352","article-title":"Large-scale analysis of longitudinal skin gene expression in systemic sclerosis reveals relationships of immune cell and fibroblast activity with skin thickness and a trend towards normalisation over time","volume":"81","author":"Skaug","year":"2022","journal-title":"Ann Rheum Dis"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.18632\/aging.204435","article-title":"Single nuclei profiling identifies cell specific markers of skeletal muscle aging, frailty, and senescence","volume":"14","author":"Perez","year":"2022","journal-title":"Aging"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780230510","article-title":"Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee","volume":"23","year":"1980","journal-title":"Arthritis Rheum"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/ageing\/afq034","article-title":"Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People","volume":"39","author":"Cruz-Jentoft","year":"2010","journal-title":"Age Ageing"},{"key":"B24","doi-asserted-by":"publisher","first-page":"795624","DOI":"10.1155\/2014\/795624","article-title":"SVM-RFE based feature selection and Taguchi parameters optimization for multiclass SVM classifier","volume":"2014","author":"Huang","year":"2014","journal-title":"ScientificWorldJournal"},{"key":"B25","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.jamda.2013.11.025","article-title":"Sarcopenia in Asia: consensus report of the Asian Working Group for Sarcopenia","volume":"15","author":"Chen","year":"2014","journal-title":"J Am Med Directors Assoc"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3337","article-title":"Robust enumeration of cell subsets from tissue expression profiles","volume":"12","author":"Newman","year":"2015","journal-title":"Nat Methods"},{"key":"B27","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1038\/s44321-024-00035-z","article-title":"Rare coding variants in NOX4 link high ROS levels to psoriatic arthritis mutilans","volume":"16","author":"Wang","year":"2024","journal-title":"EMBO Mol Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222111338","article-title":"Mitochondria as a cellular hub in infection and inflammation","volume":"22","author":"Andrieux","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2019.101122","article-title":"Implication of oxidative stress in the pathogenesis of systemic sclerosis via inflammation, autoimmunity and fibrosis","volume":"25","author":"Doridot","year":"2019","journal-title":"Redox Biol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1177\/03946320231187783","article-title":"Comprehensive analysis of ferroptosis-related hub gene signatures as a potential pathogenesis and therapeutic target for systemic sclerosis: A bioinformatics analysis","volume":"37","author":"Wu","year":"2023","journal-title":"Int J immunopathology Pharmacol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1273559","article-title":"Development and validation of a new diagnostic prediction model of ENHO and NOX4 for early diagnosis of systemic sclerosis","volume":"15","author":"Zheng","year":"2024","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0903485106","article-title":"Antioxidants prevent health-promoting effects of physical exercise in humans","volume":"106","author":"Ristow","year":"2009","journal-title":"Proc Natl Acad Sci United States America"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.158316","article-title":"NOX4 inhibition promotes the remodeling of dystrophic muscle","volume":"7","author":"Hammers","year":"2022","journal-title":"JCI Insight"},{"key":"B34","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1007\/s12094-022-02926-4","article-title":"NIMA-related kinase-6 (NEK6) as an executable target in cancer","volume":"25","author":"Panchal","year":"2023","journal-title":"Clin Trans Oncol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1080\/10715762.2018.1525712","article-title":"Oxidative\/nitrative stress in the pathogenesis of systemic sclerosis: are antioxidants beneficial","volume":"52","author":"Ames","year":"2018","journal-title":"Free Radical Res"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1007\/s11926-014-0473-0","article-title":"Role of cellular senescence and NOX4-mediated oxidative stress in systemic sclerosis pathogenesis","volume":"17","author":"Piera-Velazquez","year":"2015","journal-title":"Curr Rheumatol Rep"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/389582","article-title":"Oxidative damage and antioxidative therapy in systemic sclerosis","volume":"2014","author":"Grygiel-G\u00f3rniak","year":"2014","journal-title":"Mediators Inflammation"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2021.03.009","article-title":"Peripheral cells from patients with systemic sclerosis disease co-expressing M1 and M2 monocyte\/macrophage surface markers: Relation to the degree of skin involvement","volume":"82","author":"Mohamed","year":"2021","journal-title":"Hum Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.999008","article-title":"Dysregulated B cell function and disease pathogenesis in systemic sclerosis","volume":"13","author":"Beesley","year":"2023","journal-title":"Front Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1642806\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T05:22:05Z","timestamp":1757049725000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1642806\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,5]]},"references-count":39,"alternative-id":["10.3389\/fimmu.2025.1642806"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1642806","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,5]]},"article-number":"1642806"}}