{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:09:02Z","timestamp":1790644142537,"version":"4.1.0"},"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003819","name":"Natural Science Foundation of Hubei Province","doi-asserted-by":"publisher","award":["No. 2024AFD275"],"award-info":[{"award-number":["No. 2024AFD275"]}],"id":[{"id":"10.13039\/501100003819","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Hubei University of Chinese MEdicine","award":["No. 2022ZZXT003"],"award-info":[{"award-number":["No. 2022ZZXT003"]}]}],"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>Sex hormones play critical roles in the pathogenesis and progression of osteoarthritis (OA), yet the hormone-related molecular networks remain poorly defined. This study aimed to identify candidate sex hormone-associated genes in OA and to explore their potential functional enrichment and immune-related characteristics using bioinformatics analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>OA gene expression data were obtained from the GEO database and integrated with candidate sex hormone-associated genes retrieved from GeneCards. The R package \u201climma\u201d was then used to identify differentially expressed genes (DEGs) and sex hormone-associated DEGs (SADEGs). OA-associated SADEGs, termed OA-SADEGs, were selected using weighted gene co-expression network analysis (WGCNA), and their potential biological functions and pathways were explored by GO and KEGG enrichment analyses. Hub genes were identified using three machine learning models. xCell analysis was used to estimate immune infiltration and its associations with hub genes, and hub gene expression was further evaluated in external datasets and peripheral blood samples.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified 32 sex hormone-associated genes in OA, enriched in extracellular matrix remodeling, receptor signaling, and antigen presentation pathways. Three candidate hub genes (LOXL1, HLA-DRA, and CYBB) were consistently upregulated in OA and showed significant correlations with immune infiltration scores. xCell analysis identified 13 differentially enriched immune cell types, of which three were associated with hub genes. External dataset analysis and peripheral blood qRT-PCR showed upregulation of LOXL1, HLA-DRA, and CYBB in OA samples.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study integrated bioinformatics and immune analyses to identify candidate sex hormone-associated genes in OA. These findings provide associative bioinformatics evidence for sex hormone-associated molecular features in OA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0351556","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T17:25:49Z","timestamp":1781285149000},"page":"e0351556","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of candidate sex hormone-associated genes and immune infiltration characteristics in osteoarthritis based on bioinformatics analysis and machine learning"],"prefix":"10.1371","volume":"21","author":[{"given":"Yishu","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuna","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoxiang","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunzhou","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingliang","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xugui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongzeng","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4429-0500","authenticated-orcid":true,"given":"Chengwu","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"issue":"1","key":"pone.0351556.ref001","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.joca.2021.05.007","article-title":"The burden of OA-health services and economics","volume":"30","author":"VP Leifer","year":"2022","journal-title":"Osteoarthritis Cartilage"},{"issue":"1","key":"pone.0351556.ref002","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41572-025-00594-6","article-title":"Osteoarthritis","volume":"11","author":"S Tang","year":"2025","journal-title":"Nat Rev Dis Primers"},{"issue":"9","key":"pone.0351556.ref003","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.joca.2024.04.002","article-title":"Sex differences in osteoarthritis prevalence, pain perception, physical function and therapeutics","volume":"32","author":"NA Segal","year":"2024","journal-title":"Osteoarthritis Cartilage"},{"issue":"5","key":"pone.0351556.ref004","doi-asserted-by":"crossref","first-page":"2767","DOI":"10.3390\/ijms23052767","article-title":"Gender-related aspects in osteoarthritis development and progression: A review","volume":"23","author":"M Peshkova","year":"2022","journal-title":"Int J Mol Sci"},{"issue":"18","key":"pone.0351556.ref005","article-title":"Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations","volume":"184","author":"CG Boer","year":"2021","journal-title":"Cell"},{"issue":"4","key":"pone.0351556.ref006","doi-asserted-by":"crossref","DOI":"10.1016\/S2665-9913(23)00060-7","article-title":"The influence of sex hormones on musculoskeletal pain and osteoarthritis","volume":"5","author":"M Gulati","year":"2023","journal-title":"Lancet Rheumatol"},{"issue":"1","key":"pone.0351556.ref007","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s10020-021-00270-x","article-title":"Estrogen-related receptors: Novel potential regulators of osteoarthritis pathogenesis","volume":"27","author":"J Tang","year":"2021","journal-title":"Mol Med"},{"key":"pone.0351556.ref008","doi-asserted-by":"crossref","first-page":"683226","DOI":"10.3389\/fendo.2021.683226","article-title":"Sex steroids and osteoarthritis: A Mendelian randomization study","volume":"12","author":"Y-S Yan","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"1","key":"pone.0351556.ref009","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s12891-024-08272-6","article-title":"Correlation between low testosterone levels and the risk of osteoarthritis: A cross-sectional analysis of NHANES data (2011-2016)","volume":"26","author":"N Ma","year":"2025","journal-title":"BMC Musculoskelet Disord"},{"key":"pone.0351556.ref010","doi-asserted-by":"crossref","first-page":"9983652","DOI":"10.1155\/2021\/9983652","article-title":"Efficient automated disease diagnosis using machine learning models","volume":"2021","author":"N Kumar","year":"2021","journal-title":"J Healthc Eng"},{"issue":"6","key":"pone.0351556.ref011","doi-asserted-by":"crossref","first-page":"2903","DOI":"10.3390\/ijms22062903","article-title":"Incorporating machine learning into established bioinformatics frameworks","volume":"22","author":"N Auslander","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"2","key":"pone.0351556.ref012","article-title":"CWGCNA: An R package to perform causal inference from the WGCNA framework","volume":"6","author":"Y Liu","year":"2024","journal-title":"NAR Genom Bioinform"},{"issue":"2","key":"pone.0351556.ref013","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/s41584-021-00724-w","article-title":"Mechanosignalling in cartilage: An emerging target for the treatment of osteoarthritis","volume":"18","author":"T Hodgkinson","year":"2022","journal-title":"Nat Rev Rheumatol"},{"issue":"11","key":"pone.0351556.ref014","doi-asserted-by":"crossref","first-page":"6316","DOI":"10.3390\/ijms23116316","article-title":"Cartilage homeostasis and osteoarthritis","volume":"23","author":"Y Fujii","year":"2022","journal-title":"Int J Mol Sci"},{"issue":"809","key":"pone.0351556.ref015","doi-asserted-by":"crossref","DOI":"10.1126\/scisignal.adj9760","article-title":"Integrin-dependent recruitment of Src to ROS-producing endosomes in osteoarthritic cartilage","volume":"16","author":"MB Goldring","year":"2023","journal-title":"Sci Signal"},{"key":"pone.0351556.ref016","doi-asserted-by":"crossref","first-page":"102080","DOI":"10.1016\/j.arr.2023.102080","article-title":"Undenatured type II collagen and its role in improving osteoarthritis","volume":"91","author":"R Xu","year":"2023","journal-title":"Ageing Res Rev"},{"issue":"4","key":"pone.0351556.ref017","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.3390\/ijms22041742","article-title":"Overview of MMP-13 as a promising target for the treatment of osteoarthritis","volume":"22","author":"Q Hu","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"1","key":"pone.0351556.ref018","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1186\/s13018-023-04384-2","article-title":"Identification of sulfur metabolism-related gene signature in osteoarthritis and TM9SF2\u2019s sustenance effect on M2 macrophages\u2019 phagocytic activity","volume":"19","author":"S Zheng","year":"2024","journal-title":"J Orthop Surg Res"},{"key":"pone.0351556.ref019","doi-asserted-by":"crossref","first-page":"1164137","DOI":"10.3389\/fimmu.2023.1164137","article-title":"Effects of synovial macrophages in osteoarthritis","volume":"14","author":"K Zhao","year":"2023","journal-title":"Front Immunol"},{"issue":"2","key":"pone.0351556.ref020","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/jor.24457","article-title":"Role of inflammation and the immune system in the progression of osteoarthritis","volume":"38","author":"JE Woodell-May","year":"2020","journal-title":"J Orthop Res"},{"issue":"4","key":"pone.0351556.ref021","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.3390\/ijms22041568","article-title":"Critical role of estrogens on bone homeostasis in both male and female: From physiology to medical implications","volume":"22","author":"N-E Emmanuelle","year":"2021","journal-title":"Int J Mol Sci"},{"key":"pone.0351556.ref022","doi-asserted-by":"crossref","first-page":"107627","DOI":"10.1016\/j.phrs.2025.107627","article-title":"Promising LOX proteins for cartilage-targeting osteoarthritis therapy","volume":"212","author":"L Morici","year":"2025","journal-title":"Pharmacol Res"},{"issue":"1","key":"pone.0351556.ref023","first-page":"928","article-title":"Mechanism of lysine oxidase-like 1 promoting synovial inflammation mediating rheumatoid arthritis development","volume":"16","author":"J Hu","year":"2024","journal-title":"Aging (Albany NY)"},{"issue":"8","key":"pone.0351556.ref024","doi-asserted-by":"crossref","first-page":"5240","DOI":"10.1167\/iovs.11-7287","article-title":"Transforming growth factor-beta induces extracellular matrix protein cross-linking lysyl oxidase (LOX) genes in human trabecular meshwork cells","volume":"52","author":"A Sethi","year":"2011","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"1","key":"pone.0351556.ref025","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1186\/s12931-018-0861-5","article-title":"Transforming growth factor beta1 targets estrogen receptor signaling in bronchial epithelial cells","volume":"19","author":"LC Smith","year":"2018","journal-title":"Respir Res"},{"issue":"7","key":"pone.0351556.ref026","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1038\/s41590-019-0378-1","article-title":"Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry","volume":"20","author":"F Zhang","year":"2019","journal-title":"Nat Immunol"},{"issue":"5","key":"pone.0351556.ref027","doi-asserted-by":"crossref","first-page":"364","DOI":"10.3109\/08916934.2012.665528","article-title":"B cells as effectors and regulators of sex-biased arthritis","volume":"45","author":"D Luckey","year":"2012","journal-title":"Autoimmunity"},{"key":"pone.0351556.ref028","doi-asserted-by":"crossref","first-page":"110452","DOI":"10.1016\/j.biopha.2020.110452","article-title":"Oxidative stress and inflammation in osteoarthritis pathogenesis: Role of polyphenols","volume":"129","author":"MY Ansari","year":"2020","journal-title":"Biomed Pharmacother"},{"key":"pone.0351556.ref029","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.jot.2020.09.006","article-title":"Chondrocyte ferroptosis contribute to the progression of osteoarthritis","volume":"27","author":"X Yao","year":"2020","journal-title":"J Orthop Translat"},{"issue":"12","key":"pone.0351556.ref030","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1016\/j.joca.2018.08.014","article-title":"The role of NOX2-derived reactive oxygen species in collagenase-induced osteoarthritis","volume":"26","author":"SCM van Dalen","year":"2018","journal-title":"Osteoarthritis Cartilage"},{"key":"pone.0351556.ref031","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.steroids.2017.12.010","article-title":"Sex-related differences in oxidative stress and neurodegeneration","volume":"133","author":"MA Tenkorang","year":"2018","journal-title":"Steroids"},{"issue":"23","key":"pone.0351556.ref032","doi-asserted-by":"crossref","first-page":"7304","DOI":"10.3390\/jcm12237304","article-title":"Oxidative Stress: The Role of Estrogen and Progesterone","volume":"12","author":"A Cagnacci","year":"2023","journal-title":"J Clin Med"},{"issue":"5","key":"pone.0351556.ref033","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.joca.2020.01.007","article-title":"Macrophages regulate the progression of osteoarthritis","volume":"28","author":"H Zhang","year":"2020","journal-title":"Osteoarthritis Cartilage"},{"issue":"6","key":"pone.0351556.ref034","first-page":"5009","article-title":"Imbalance of M1\/M2 macrophages is linked to severity level of knee osteoarthritis","volume":"16","author":"B Liu","year":"2018","journal-title":"Exp Ther Med"},{"key":"pone.0351556.ref035","doi-asserted-by":"crossref","first-page":"1393418","DOI":"10.3389\/fimmu.2024.1393418","article-title":"The role of Th\/Treg immune cells in osteoarthritis","volume":"15","author":"Z Wen","year":"2024","journal-title":"Front Immunol"},{"issue":"5","key":"pone.0351556.ref036","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1080\/08820139.2024.2337025","article-title":"Insights into the roles of natural killer cells in osteoarthritis","volume":"53","author":"C-Q Zheng","year":"2024","journal-title":"Immunol Invest"},{"issue":"5","key":"pone.0351556.ref037","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.4049\/jimmunol.1601359","article-title":"CXCR3\/CXCL10 axis regulates neutrophil-NK cell cross-talk determining the severity of experimental osteoarthritis","volume":"198","author":"G Benigni","year":"2017","journal-title":"J Immunol"},{"issue":"17","key":"pone.0351556.ref038","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.3390\/cells13171420","article-title":"Upregulation of mitochondrial Sirt3 and alleviation of the inflammatory phenotype in macrophages by estrogen","volume":"13","author":"ML Barcena","year":"2024","journal-title":"Cells"},{"issue":"11","key":"pone.0351556.ref039","doi-asserted-by":"crossref","first-page":"5021","DOI":"10.1210\/en.2004-0619","article-title":"Estrogen modulates microglial inflammatory mediator production via interactions with estrogen receptor beta","volume":"145","author":"AE Baker","year":"2004","journal-title":"Endocrinology"},{"issue":"1","key":"pone.0351556.ref040","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.imlet.2010.07.001","article-title":"Sex hormones and autoimmunity","volume":"133","author":"DA Gonz\u00e1lez","year":"2010","journal-title":"Immunol Lett"},{"key":"pone.0351556.ref041","doi-asserted-by":"crossref","first-page":"103263","DOI":"10.1016\/j.jaut.2024.103263","article-title":"Inflammation dynamically regulates steroid hormone metabolism and action within macrophages in rheumatoid arthritis","volume":"147","author":"CS Martin","year":"2024","journal-title":"J Autoimmun"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0351556","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T17:25:59Z","timestamp":1781285159000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0351556"}},"subtitle":[],"editor":[{"given":"Gianpaolo","family":"Papaccio","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,6,12]]},"references-count":41,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6,12]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0351556","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,12]]}}}