{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T23:12:31Z","timestamp":1791846751319,"version":"4.3.4"},"reference-count":39,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T00:00:00Z","timestamp":1736985600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health and Family Planning Commission of Hebei Province, China","award":["20231597"],"award-info":[{"award-number":["20231597"]}]},{"DOI":"10.13039\/501100003787","name":"Hebei Natural Science Foundation","doi-asserted-by":"crossref","award":["H2022106047"],"award-info":[{"award-number":["H2022106047"]}],"id":[{"id":"10.13039\/501100003787","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Endometriosis is a chronic inflammatory disorder characterized by presence of endometrial tissue outside the uterine cavity. Immunohistochemical analysis (IHC) revealed markedly elevated expression of <jats:italic>IL6ST<\/jats:italic> in endometrial tissue of patients with ovarian endometriosis. Level of methylation of <jats:italic>IL6ST<\/jats:italic> is diminished in patients with endometriosis, whereas level of mRNA expression is markedly elevated by RT-PCR. Cell Counting Kit-8, Transwell, Terminal deoxynucleotidyl transferase dUTP nick end labeling assays substantiated endometrial stromal cells stably transfected with 3*FLAG-<jats:italic>IL6ST<\/jats:italic> plasmid exhibited enhanced viability, augmented invasive capacity, and notable reduction in apoptosis rates. Furthermore, <jats:italic>IL6ST<\/jats:italic> facilitated progression of endometriosis by activating mitogen-activated protein kinase 9\/Signal Transducer and Activator of Transcription 3 signaling pathway. Western blot analysis revealed significantly elevated protein levels of p-JAK2\/JAK2, p-STAT3\/STAT3, HIF-1\u03b1, and VEGF in <jats:italic>IL6ST<\/jats:italic> overexpression group. Conversely, JAK2\/STAT3 inhibitor WP1066 had markedly reduced p-JAK2 and p-STAT3 protein levels in <jats:italic>IL6ST<\/jats:italic> overexpression group. Inhibiting JAK2\/STAT3 signaling pathway had mitigating effect on proliferative and invasive enhancement of endometrial stromal cells, as well as inhibition of apoptosis induced by <jats:italic>IL6ST<\/jats:italic>. These findings offer novel potential targets and strategies for the treatment of endometriosis.<\/jats:p>","DOI":"10.1371\/journal.pone.0317569","type":"journal-article","created":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T18:32:38Z","timestamp":1737052358000},"page":"e0317569","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Hypomethylation of IL6ST promotes development of endometriosis by activating JAK2\/STAT3 signaling pathway"],"prefix":"10.1371","volume":"20","author":[{"given":"Yue","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijuan","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiumei","family":"Chi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3349-9652","authenticated-orcid":true,"given":"Qinying","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,1,16]]},"reference":[{"key":"pone.0317569.ref001","doi-asserted-by":"crossref","first-page":"1020827","DOI":"10.3389\/fendo.2022.1020827","article-title":"Endometriosis-associated infertility: From pathophysiology to tailored treatment.","volume":"13","author":"G Bonavina","year":"2022","journal-title":"Frontiers in endocrinology"},{"issue":"10276","key":"pone.0317569.ref002","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/S0140-6736(21)00389-5","article-title":"Endometriosis is a chronic systemic disease: clinical challenges and novel innovations","volume":"397","author":"HS Taylor","year":"2021","journal-title":"Lancet (London, England)."},{"issue":"1","key":"pone.0317569.ref003","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1001\/jama.2021.4788","article-title":"Diagnosis and Management of Infertility: A Review","volume":"326","author":"SA Carson","year":"2021","journal-title":"Jama"},{"issue":"9","key":"pone.0317569.ref004","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1001\/jama.2009.1268","article-title":"Laparoscopic uterosacral nerve ablation for alleviating chronic pelvic pain: a randomized controlled trial","volume":"302","author":"J Daniels","year":"2009","journal-title":"Jama"},{"issue":"2","key":"pone.0317569.ref005","first-page":"824","article-title":"Tumor necrosis factor-alpha promotes proliferation of endometriotic stromal cells by inducing interleukin-8 gene and protein expression","volume":"85","author":"T Iwabe","year":"2000","journal-title":"The Journal of clinical endocrinology and metabolism"},{"issue":"17","key":"pone.0317569.ref006","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1007\/s40265-023-01951-z","article-title":"The Place of Cannabinoids in the Treatment of Gynecological Pain.","volume":"83","author":"J Sinclair","year":"2023","journal-title":"Drugs"},{"issue":"3","key":"pone.0317569.ref007","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S0377-1237(10)80039-5","article-title":"Treatment of Endometriosis and Chronic Pelvic Pain with Letrozole and Norethindrone Acetate.","volume":"66","author":"S. Chawla","year":"2010","journal-title":"Medical journal, Armed Forces India."},{"issue":"6","key":"pone.0317569.ref008","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1093\/humrep\/deu074","article-title":"Regression of endothelial dysfunction in patients with endometriosis after surgical treatment: a 2-year follow-up study","volume":"29","author":"L Santoro","year":"2014","journal-title":"Human reproduction (Oxford, England)."},{"issue":"1","key":"pone.0317569.ref009","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1093\/humupd\/dmad025","article-title":"Transcriptomic integrity of human oocytes used in ARTs: technical and intrinsic factor effects","volume":"30","author":"B Ducreux","year":"2024","journal-title":"Human reproduction update"},{"issue":"4","key":"pone.0317569.ref010","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1093\/humupd\/dmp007","article-title":"Recurrence of endometriosis and its control","volume":"15","author":"SW Guo","year":"2009","journal-title":"Human reproduction update"},{"key":"pone.0317569.ref011","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13148-015-0168-z","article-title":"The influence of menstrual cycle and endometriosis on endometrial methylome.","volume":"8","author":"M Saare","year":"2016","journal-title":"Clinical epigenetics.PubMed Central PMCID"},{"issue":"1","key":"pone.0317569.ref012","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1038\/s42003-023-05070-z","article-title":"Global endometrial DNA methylation analysis reveals insights into mQTL regulation and associated endometriosis disease risk and endometrial function","volume":"6","author":"S Mortlock","year":"2023","journal-title":"Communications biology"},{"issue":"6","key":"pone.0317569.ref013","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1210\/endrev\/bnad020","article-title":"Epigenetic Dysregulation in Endometriosis: Implications for Pathophysiology and Therapeutics","volume":"44","author":"RM Marquardt","year":"2023","journal-title":"Endocrine reviews"},{"issue":"5","key":"pone.0317569.ref014","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1007\/s43032-021-00751-8","article-title":"Identification of Key Differentially Methylated\/Expressed Genes and Pathways for Ovarian Endometriosis by Bioinformatics Analysis.","volume":"29","author":"H Zhang","year":"2022","journal-title":"Reproductive sciences (Thousand Oaks, Calif)."},{"issue":"6","key":"pone.0317569.ref015","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1182\/blood-2007-01-067918","article-title":"Apoptosis is a natural stimulus of IL6R shedding and contributes to the proinflammatory trans-signaling function of neutrophils","volume":"110","author":"A Chalaris","year":"2007","journal-title":"Blood"},{"issue":"1","key":"pone.0317569.ref016","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1080\/15592294.2021.1876285","article-title":"DNA methylation profile of genes involved in inflammation and autoimmunity correlates with vascular function in morbidly obese adults","volume":"17","author":"MM Ali","year":"2022","journal-title":"Epigenetics"},{"key":"pone.0317569.ref017","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.biocel.2014.08.005","article-title":"Stearoyl-CoA desaturase regulates inflammatory gene expression by changing DNA methylation level in 3T3 adipocytes","volume":"55","author":"M Malodobra-Mazur","year":"2014","journal-title":"The international journal of biochemistry & cell biology"},{"issue":"4","key":"pone.0317569.ref018","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1042\/CS20110340","article-title":"IL-6\/IL-6 receptor system and its role in physiological and pathological conditions","volume":"122","author":"M Mihara","year":"2012","journal-title":"Clinical science (London, England: 1979)."},{"issue":"9","key":"pone.0317569.ref019","doi-asserted-by":"crossref","first-page":"4078","DOI":"10.7150\/thno.52574","article-title":"Electroacupuncture ameliorates intestinal inflammation by activating \u03b17nAChR-mediated JAK2\/STAT3 signaling pathway in postoperative ileus.","volume":"11","author":"NN Yang","year":"2021","journal-title":"Theranostics"},{"issue":"2","key":"pone.0317569.ref020","doi-asserted-by":"crossref","DOI":"10.3390\/biomedicines9020187","article-title":"STAT3 Signalling via the IL-6ST\/gp130 Cytokine Receptor Promotes Epithelial Integrity and Intestinal Barrier Function during DSS-Induced Colitis.","volume":"9","author":"L Pang","year":"2021","journal-title":"Biomedicines"},{"issue":"8","key":"pone.0317569.ref021","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1007\/s43032-023-01202-2","article-title":"Effects of STAT Inhibitors in Mouse Models of Endometriosis.","volume":"30","author":"H Inui","year":"2023","journal-title":"Reproductive sciences (Thousand Oaks, Calif)."},{"key":"pone.0317569.ref022","doi-asserted-by":"crossref","first-page":"154404","DOI":"10.1016\/j.prp.2023.154404","article-title":"Identification of key modules and candidate genes associated with endometriosis based on transcriptome data via bioinformatics analysis","volume":"244","author":"W Zheng","year":"2023","journal-title":"Pathology, research and practice."},{"issue":"10","key":"pone.0317569.ref023","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1177\/1933719114532841","article-title":"Altered genome-wide methylation in endometriosis.","volume":"21","author":"H Naqvi","year":"2014","journal-title":"Reproductive sciences (Thousand Oaks, Calif)."},{"issue":"1","key":"pone.0317569.ref024","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.fertnstert.2020.08.1398","article-title":"Insight into epigenetics of human endometriosis organoids: DNA methylation analysis of HOX genes and their cofactors","volume":"115","author":"F Esfandiari","year":"2021","journal-title":"Fertility and sterility"},{"key":"pone.0317569.ref025","doi-asserted-by":"crossref","first-page":"1093683","DOI":"10.3389\/fendo.2023.1093683","article-title":"Integrated analysis of genome-wide gene expression and DNA methylation profiles reveals candidate genes in ovary endometriosis","volume":"14","author":"L Lei","year":"2023","journal-title":"Frontiers in endocrinology"},{"issue":"6","key":"pone.0317569.ref026","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1002\/mrd.23139","article-title":"Aberrant methylation of the IL-12B promotor region contributes to the risk of developing ovarian endometriosis","volume":"86","author":"W Zhao","year":"2019","journal-title":"Molecular reproduction and development"},{"issue":"2","key":"pone.0317569.ref027","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.ajog.2005.01.034","article-title":"Aberrant methylation at HOXA10 may be responsible for its aberrant expression in the endometrium of patients with endometriosis","volume":"193","author":"Y Wu","year":"2005","journal-title":"American journal of obstetrics and gynecology"},{"issue":"5","key":"pone.0317569.ref028","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1002\/jcb.10464","article-title":"Expression of various genes is controlled by DNA methylation during mammalian development","volume":"88","author":"M. Ehrlich","year":"2003","journal-title":"Journal of cellular biochemistry"},{"issue":"2","key":"pone.0317569.ref029","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/s41419-024-06495-y","article-title":"Farnesoid X receptor promotes non-small cell lung cancer metastasis by activating Jak2\/STAT3 signaling via transactivation of IL-6ST and IL-6 genes.","volume":"15","author":"X Jin","year":"2024","journal-title":"Cell Death Dis."},{"issue":"1","key":"pone.0317569.ref030","doi-asserted-by":"crossref","first-page":"22756","DOI":"10.1038\/s41598-021-01950-8","article-title":"Evaluation of selected IL6\/STAT3 pathway molecules and miRNA expression in chronic obstructive pulmonary disease.","volume":"11","author":"JM Kisza\u0142kiewicz","year":"2021","journal-title":"Scientific reports."},{"key":"pone.0317569.ref031","doi-asserted-by":"crossref","first-page":"761300","DOI":"10.3389\/fcell.2021.761300","article-title":"Single-Cell RNA Sequencing Revealed CD14(+) Monocytes Increased in Patients With Takayasu\u2019s Arteritis Requiring Surgical Management.","volume":"9","author":"G Qing","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"pone.0317569.ref032","doi-asserted-by":"crossref","first-page":"3801","DOI":"10.12659\/MSM.905226","article-title":"Role of Interleukin-6 and Its Receptor in Endometriosis","volume":"23","author":"S Li","year":"2017","journal-title":"Medical science monitor: international medical journal of experimental and clinical research"},{"issue":"9","key":"pone.0317569.ref033","doi-asserted-by":"crossref","first-page":"3450","DOI":"10.1210\/jc.2014-1026","article-title":"Transforming growth factor-\u03b2 induced Warburg-like metabolic reprogramming may underpin the development of peritoneal endometriosis","volume":"99","author":"VJ Young","year":"2014","journal-title":"The Journal of clinical endocrinology and metabolism"},{"key":"pone.0317569.ref034","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.2147\/IJN.S354314","article-title":"Exosomal lncRNA HOTAIR Promotes the Progression and Angiogenesis of Endometriosis via the miR-761\/HDAC1 Axis and Activation of STAT3-Mediated Inflammation.","volume":"17","author":"L Zhang","year":"2022","journal-title":"International journal of nanomedicine"},{"issue":"1","key":"pone.0317569.ref035","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/s42003-021-02018-z","article-title":"Regulatory T cells induce polarization of pro-repair macrophages by secreting sFGL2 into the endometriotic milieu","volume":"4","author":"XX Hou","year":"2021","journal-title":"Communications biology"},{"issue":"10","key":"pone.0317569.ref036","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1093\/molehr\/gav039","article-title":"Leptin promotes human endometriotic cell migration and invasion by up-regulating MMP-2 through the JAK2\/STAT3 signaling pathway","volume":"21","author":"JH Ahn","year":"2015","journal-title":"Mol Hum Reprod"},{"issue":"1","key":"pone.0317569.ref037","first-page":"46","article-title":"Interaction of macrophages and endometrial cells induces epithelial-mesenchymal transition-like processes in adenomyosis","volume":"96","author":"M An","year":"2017","journal-title":"Biology of reproduction"},{"issue":"21","key":"pone.0317569.ref038","doi-asserted-by":"crossref","first-page":"12656","DOI":"10.1111\/jcmm.15833","article-title":"Circ_0007331 knock-down suppresses the progression of endometriosis via miR-200c-3p\/HiF-1\u03b1 axis","volume":"24","author":"L Dong","year":"2020","journal-title":"J Cell Mol Med"},{"issue":"10","key":"pone.0317569.ref039","doi-asserted-by":"crossref","DOI":"10.3390\/pharmaceutics13101618","article-title":"Cell-Penetrating Peptide and siRNA-Mediated Therapeutic Effects on Endometriosis and Cancer In Vitro Models.","volume":"13","author":"K Kiisholts","year":"2021","journal-title":"Pharmaceutics"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0317569","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T18:32:54Z","timestamp":1737052374000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0317569"}},"subtitle":[],"editor":[{"given":"Kazunori","family":"Nagasaka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,1,16]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1,16]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0317569","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,16]]}}}