{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T02:29:19Z","timestamp":1790994559497,"version":"4.1.0"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82260391, 82372541, 82360448"],"award-info":[{"award-number":["82260391, 82372541, 82360448"]}],"id":[{"id":"10.13039\/501100001809","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>Cancer-related lymphedema (CRL) is a common chronic complication following cancer treatment, characterized by impaired lymphatic drainage, interstitial fluid retention, and progressive fibrosis. Although the mechanisms of hypertrophic scar (HTS) fibrosis have been extensively investigated, the molecular drivers of fibrosis in CRL remain unclear. Identification of reliable biomarkers and novel therapeutic targets is essential for enabling early intervention.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Transcriptomic datasets of CRL and HTS from the Gene Expression Omnibus (GEO) were integrated to identify fibrosis-associated differentially expressed genes (DEGs) and construct co-expression modules. Weighted gene co-expression network analysis (WGCNA) and protein\u2013protein interaction (PPI) network analysis were employed to nominate hub genes. Single-cell RNA sequencing (scRNA-seq) data were used to localize candidate gene expression within immune and mesenchymal cell populations. The most promising biomarker was validated in clinical CRL tissues by Masson\u2019s trichrome staining and Western blotting, and Pearson correlation analyses were performed to assess its association with collagen deposition and disease duration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 154 fibrosis-related genes were found to be shared by CRL and HTS. Among them, Asporin (ASPN) emerged as the most promising hub gene, with markedly elevated expression in late-stage CRL tissues. scRNA-seq analysis revealed that adipose-derived stem cells (ADSCs) were the predominant ASPN-expressing population. In CRL lesions, ASPN expression levels showed significant positive correlations with disease duration, TGF-\u03b2 expression, and collagen accumulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>ASPN is identified as a key molecular biomarker of fibrosis in CRL. Its predominant expression in ADSCs and strong association with progressive tissue remodeling suggest that ASPN holds potential as both a diagnostic indicator and a therapeutic target for CRL-related fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1625972","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T04:16:03Z","timestamp":1755058563000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Identification of novel hub genes and pathways predictive of fibrosis progression in cancer-related lymphedema through integrated multi-omics"],"prefix":"10.3389","volume":"16","author":[{"given":"Junzhe","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuezhong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangliang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaping","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shune","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengliang","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1097\/PRS.0000000000009866","article-title":"The vicious circle of stasis, inflammation, and fibrosis in lymphedema","volume":"151","author":"Brown","year":"2023","journal-title":"Plast Reconstr Surg"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.22684","article-title":"Lymphedema after gynecological cancer treatment: Prevalence, correlates, and supportive care needs","volume":"109","author":"Beesley","year":"2007","journal-title":"Cancer"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(13)70076-7","article-title":"Incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-analysis","volume":"14","author":"DiSipio","year":"2013","journal-title":"Lancet Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.318307","article-title":"Advances in lymphedema","volume":"128","author":"Rockson","year":"2021","journal-title":"Circ Res"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2297","DOI":"10.3390\/cancers12082297","article-title":"Lymphatic valves and lymph flow in cancer-related lymphedema","volume":"12","author":"Iyer","year":"2020","journal-title":"Cancers"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-060116-022900","article-title":"Lymphedema: pathogenesis and novel therapies","volume":"69","author":"Dayan","year":"2018","journal-title":"Annu Rev Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.21037\/gs-23-503","article-title":"Surgical treatment algorithm for breast cancer lymphedema\u2014a systematic review","volume":"13","author":"Lilja","year":"2024","journal-title":"Gland Surg"},{"key":"B8","doi-asserted-by":"publisher","first-page":"3907","DOI":"10.3390\/ijms25073907","article-title":"The role of inflammation in lymphedema: A narrative review of pathogenesis and opportunities for therapeutic intervention","volume":"25","author":"Bowman","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.873650","article-title":"Acquired lymphedema: Molecular contributors and future directions for developing intervention strategies","volume":"13","author":"Nurlaila","year":"2022","journal-title":"Front Pharmacol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1089\/wound.2021.0041","article-title":"Current understanding of pathological mechanisms of lymphedema","volume":"11","author":"Sung","year":"2022","journal-title":"Adv Wound Care"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1089\/lrb.2024.0006","article-title":"Characteristic computed tomography findings in female patients with secondary genital lymphedema","volume":"23","author":"Sumiya","year":"2025","journal-title":"Lymphat Res Biol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2024.1363811","article-title":"Molecular pathophysiology of secondary lymphedema","volume":"12","author":"Lee","year":"2024","journal-title":"Front Cell Dev Biol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1007\/s40257-022-00744-6","article-title":"Hypertrophic scars and keloids: advances in treatment and review of established therapies","volume":"24","author":"Frech","year":"2023","journal-title":"Am J Clin Dermatol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1038\/s41572-023-00474-x","article-title":"Scars","volume":"9","author":"Jeschke","year":"2023","journal-title":"Nat Rev Dis Primer"},{"key":"B15","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1038\/s41421-022-00402-5","article-title":"Single-cell RNA sequencing of subcutaneous adipose tissues identifies therapeutic targets for cancer-associated lymphedema","volume":"8","author":"Liu","year":"2022","journal-title":"Cell Discov"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1097\/PRS.0000000000010082","article-title":"The impacts of lymph on the adipogenesis of adipose-derived stem cells","volume":"151","author":"Hsiao","year":"2022","journal-title":"Plast Reconstr Surg"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202400498RR","article-title":"Multi-omics characterization of lymphedema-induced adipose tissue resulting from breast cancer-related surgery","volume":"38","author":"Karaman","year":"2024","journal-title":"FASEB J Off Publ Fed Am Soc Exp Biol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1055","article-title":"The Gene Ontology Resource: 20 years and still GOing strong","volume":"47","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B19","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"B20","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1007\/s12032-024-02576-2","article-title":"Advances in surgical management of chronic lymphedema: current strategies and future directions","volume":"42","author":"Sanka","year":"2025","journal-title":"Med Oncol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"6","DOI":"10.21037\/tbcr-24-49","article-title":"Modern approaches to lymphatic surgery: a narrative review","volume":"6","author":"Zurbuchen","year":"2025","journal-title":"Transl Breast Cancer Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1097\/PRS.0000000000011363","article-title":"Metformin eliminates lymphedema in mice by alleviating inflammation and fibrosis: implications for human therapy","volume":"154","author":"Wei","year":"2024","journal-title":"Plast Reconstr Surg"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/tmi.13359","article-title":"Human skin fibrosis: up-regulation of collagen type III gene transcription in the fibrotic skin nodules of lower limb lymphoedema","volume":"25","author":"Karayi","year":"2020","journal-title":"Trop Med Int Health TM IH"},{"key":"B24","doi-asserted-by":"publisher","first-page":"6621","DOI":"10.3390\/ijms23126621","article-title":"Current mechanistic understandings of lymphedema and lipedema: tales of fluid, fat, and fibrosis","volume":"23","author":"Duhon","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B25","doi-asserted-by":"publisher","first-page":"688e","DOI":"10.1097\/PRS.0000000000011141","article-title":"Lymphedema-associated fibroblasts are related to fibrosis and stage progression in patients and a murine microsurgical model","volume":"154","author":"Will","year":"2024","journal-title":"Plast Reconstr Surg"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000032490","article-title":"Relationship between asporin and extracellular matrix behavior: A literature review","volume":"101","author":"Fan","year":"2022","journal-title":"Med (Baltimore)"},{"key":"B27","doi-asserted-by":"publisher","first-page":"046107","DOI":"10.1063\/5.0233961","article-title":"Apoptosis-associated genetic mechanisms in the transition from rheumatoid arthritis to osteoporosis: A bioinformatics and functional analysis approach","volume":"8","author":"Lo","year":"2024","journal-title":"APL Bioeng"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2015.02.011","article-title":"Asporin and osteoarthritis","volume":"23","author":"Xu","year":"2015","journal-title":"Osteoarthr Cartil"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202100111R","article-title":"Asporin inhibits collagen matrix-mediated intercellular mechanocommunications between fibroblasts during keloid progression","volume":"35","author":"Liu","year":"2021","journal-title":"FASEB J"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2021-0257OC","article-title":"Asporin promotes TGF-\u03b2\u2013induced lung myofibroblast differentiation by facilitating rab11-dependent recycling of T\u03b2RI","volume":"66","author":"Huang","year":"2022","journal-title":"Am J Respir Cell Mol Biol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1625972\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T04:16:04Z","timestamp":1755058564000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1625972\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,13]]},"references-count":30,"alternative-id":["10.3389\/fimmu.2025.1625972"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1625972","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,13]]},"article-number":"1625972"}}