{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:45:34Z","timestamp":1791272734783,"version":"4.1.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2021,7,12]],"date-time":"2021-07-12T00:00:00Z","timestamp":1626048000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":["rep.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Deficient decidualization of endometrial stromal cells (ESCs) can cause adverse pregnancy outcomes including miscarriage, intrauterine growth restriction, and pre-eclampsia. Decidualization is regulated by multiple factors such as hormones and circadian genes. Melatonin, a circadian-controlled hormone, is reported to be important for various reproductive processes, including oocyte maturation and placenta development. Its receptor, MT1, is considered to be related to intrauterine growth restriction and pre-eclampsia. However, the role of melatonin-MT1 signal in decidualization remains unknown. Here, we reported that decidual stromal cells from miscarriages displayed deficient decidualization with decreased MT1 expression. The expression level of MT1 is gradually increased with the process of decidualization induction in vitro. MT1 knockdown suppressed the decidualization level, while the overexpression of MT1 promoted the decidualization process. Moreover, changing MT1 level could regulate the expression of decidualization-related transcription factor FOXO1. Melatonin promoted decidualization and reversed the decidualization deficiency due to MT1 knockdown. Using in vitro and in vivo experiments, we further identified that lipopolysaccharide (LPS) could induce inflammation and decidualization resistance with downregulated MT1 expression, and melatonin could reverse the inflammation and decidualization resistance induced by LPS. These results suggested that the melatonin-MT1 signal might be essential for decidualization and might provide a novel therapeutic target for decidualization deficiency-associated pregnancy complications.<\/jats:p>","DOI":"10.1530\/rep-21-0159","type":"journal-article","created":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T12:18:03Z","timestamp":1623413883000},"page":"161-170","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-11","source":"Crossref","is-referenced-by-count":14,"title":["Melatonin-MT1 signal is essential for endometrial decidualization"],"prefix":"10.1093","volume":"162","author":[{"given":"Liyuan","family":"Cui","sequence":"first","affiliation":[{"name":"NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research) , Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases , Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Xu","sequence":"additional","affiliation":[{"name":"NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research) , Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases , Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songcun","family":"Wang","sequence":"additional","affiliation":[{"name":"NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research) , Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases , Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuxuan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics , The first People\u2019s Hospital of Yangzhou, Yangzhou Medical University, Yangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Liu","sequence":"additional","affiliation":[{"name":"NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research) , Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases , Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Ding","sequence":"additional","affiliation":[{"name":"NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research) , Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases , Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology , Center of Reproductive Medicine, Affiliated Hospital of Nantong University, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5307-6784","authenticated-orcid":false,"given":"Meirong","family":"Du","sequence":"additional","affiliation":[{"name":"NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research) , Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases , Shanghai, China"},{"name":"Department of Obstetrics and Gynecology , Guangzhou First People\u2019s Hospital, School of Medicine, South China University of Technology, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,7,12]]},"reference":[{"key":"2026010712065337700_bib1","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1210\/en.2010-0899","article-title":"NADPH oxidase-derived reactive oxygen species mediate decidualization of human endometrial stromal cells in response to cyclic AMP signaling","volume":"152","author":"Al-Sabbagh","year":"2011","journal-title":"Endocrinology"},{"key":"2026010712065337700_bib2","doi-asserted-by":"publisher","first-page":"1244","DOI":"10.1093\/biolre\/iox053","article-title":"Melatonin protects against cisplatin-induced ovarian damage in mice via the MT1 receptor and antioxidant activity","volume":"96","author":"Barberino","year":"2017","journal-title":"Biology of Reproduction"},{"key":"2026010712065337700_bib3","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1016\/j.ogc.2016.07.004","article-title":"Immune regulation in pregnancy: a matter of perspective?","volume":"43","author":"Bonney","year":"2016","journal-title":"Obstetrics and Gynecology Clinics of North America"},{"key":"2026010712065337700_bib4","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.1067\/mob.2002.127305","article-title":"The myometrial junctional zone spiral arteries in normal and abnormal pregnancies: a review of the literature","volume":"187","author":"Brosens","year":"2002","journal-title":"American Journal of Obstetrics and Gynecology"},{"key":"2026010712065337700_bib5","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/j.phrs.2019.04.015","article-title":"Melatonin MT1 receptor as a novel target in neuropsychopharmacology: MT1 ligands, pathophysiological and therapeutic implications, and perspectives","volume":"144","author":"Comai","year":"2019","journal-title":"Pharmacological Research"},{"key":"2026010712065337700_bib6","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1016\/j.fertnstert.2007.03.050","article-title":"Effects of melatonin on the endometrial morphology and embryo implantation in rats","volume":"89","author":"Dair","year":"2008","journal-title":"Fertility and Sterility"},{"key":"2026010712065337700_bib7","doi-asserted-by":"publisher","first-page":"9623","DOI":"10.1523\/JNEUROSCI.1391-07.2007","article-title":"Responses of suprachiasmatic nucleus neurons to light and dark adaptation: relative contributions of melanopsin and rod-cone inputs","volume":"27","author":"Drouyer","year":"2007","journal-title":"Journal of Neuroscience"},{"key":"2026010712065337700_bib8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1600-079X.2011.00916.x","article-title":"Melatonin as a natural ally against oxidative stress: a physicochemical examination","volume":"51","author":"Galano","year":"2011","journal-title":"Journal of Pineal Research"},{"key":"2026010712065337700_bib9","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1111\/jpi.12010","article-title":"On the free radical scavenging activities of melatonin\u2019s metabolites, AFMK and AMK","volume":"54","author":"Galano","year":"2013","journal-title":"Journal of Pineal Research"},{"key":"2026010712065337700_bib10","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1677\/joe.0.1780357","article-title":"Cyclic AMP and progesterone receptor cross-talk in human endometrium: a decidualizing affair","volume":"178","author":"Gellersen","year":"2003","journal-title":"Journal of Endocrinology"},{"key":"2026010712065337700_bib11","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1111\/jpi.12345","article-title":"Melatonin and its receptor MT1 are involved in the downstream reaction to luteinizing hormone and participate in the regulation of luteinization in different species","volume":"61","author":"He","year":"2016","journal-title":"Journal of Pineal Research"},{"key":"2026010712065337700_bib12","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1023\/a:1016618405570","article-title":"Seasonal changes in human sperm chromatin condensation","volume":"18","author":"Henkel","year":"2001","journal-title":"Journal of Assisted Reproduction and Genetics"},{"key":"2026010712065337700_bib13","doi-asserted-by":"publisher","DOI":"10.1038\/nature05993","article-title":"p53 regulates maternal reproduction through LIF","volume":"450","author":"Hu","year":"2007","journal-title":"Nature"},{"key":"2026010712065337700_bib14","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-019-1490-8","article-title":"Fetal liver mesenchymal stem cells restore ovarian function in premature ovarian insufficiency by targeting MT1","volume":"10","author":"Huang","year":"2019","journal-title":"Stem Cell Research and Therapy"},{"key":"2026010712065337700_bib15","doi-asserted-by":"publisher","first-page":"2444","DOI":"10.1210\/me.2006-0118","article-title":"Differential expression of FOXO1 and FOXO3a confers resistance to oxidative cell death upon endometrial decidualization","volume":"20","author":"Kajihara","year":"2006","journal-title":"Molecular Endocrinology"},{"key":"2026010712065337700_bib16","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1139\/cjpp-2015-0003","article-title":"TIIA attenuates LPS-induced mouse endometritis by suppressing the NF-kappaB signaling pathway","volume":"93","author":"Lv","year":"2015","journal-title":"Canadian Journal of Physiology and Pharmacology"},{"key":"2026010712065337700_bib17","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1093\/biolre\/ioz063","article-title":"Impaired decidualization caused by downregulation of circadian clock gene BMAL1 contributes to human recurrent miscarriagedagger","volume":"101","author":"Lv","year":"2019","journal-title":"Biology of Reproduction"},{"key":"2026010712065337700_bib18","doi-asserted-by":"publisher","first-page":"1755","DOI":"10.1093\/humrep\/dew099","article-title":"Endometrial preparation: effect of estrogen dose and administration route on reproductive outcomes in oocyte donation cycles with fresh embryo transfer","volume":"31","author":"Madero","year":"2016","journal-title":"Human Reproduction"},{"key":"2026010712065337700_bib19","doi-asserted-by":"publisher","first-page":"1870","DOI":"10.1073\/pnas.0507261103","article-title":"C\/EBP beta is a critical mediator of steroid hormone-regulated cell proliferation and differentiation in the uterine epithelium and stroma","volume":"103","author":"Mantena","year":"2006","journal-title":"PNAS"},{"key":"2026010712065337700_bib20","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1007\/s00441-008-0734-1","article-title":"In vitro decidualization of rat endometrial stromal cells","volume":"335","author":"Matsumoto","year":"2009","journal-title":"Cell and Tissue Research"},{"key":"2026010712065337700_bib21","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1530\/REP-18-0417","article-title":"CXCL16\/CXCR6 interaction promotes endometrial decidualization via the PI3K\/AKT pathway","volume":"157","author":"Mei","year":"2019","journal-title":"Reproduction"},{"key":"2026010712065337700_bib22","doi-asserted-by":"publisher","first-page":"9174521","DOI":"10.1155\/2019\/9174521","article-title":"New insights into the process of placentation and the role of oxidative uterine microenvironment","volume":"2019","author":"Mendes","year":"2019","journal-title":"Oxidative Medicine and Cellular Longevity"},{"key":"2026010712065337700_bib23","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/j.fertnstert.2019.02.008","article-title":"Uterine polyps, adenomyosis, leiomyomas, and endometrial receptivity","volume":"111","author":"Munro","year":"2019","journal-title":"Fertility and Sterility"},{"key":"2026010712065337700_bib24","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1177\/1933719112442244","article-title":"Melatonin and the circadian timing of human parturition","volume":"20","author":"Olcese","year":"2013","journal-title":"Reproductive Sciences"},{"key":"2026010712065337700_bib25","doi-asserted-by":"publisher","first-page":"3161","DOI":"10.1093\/molbev\/msw193","article-title":"Cis-regulatory evolution of forkhead Box O1 (FOXO1), a terminal selector gene for decidual stromal cell identity","volume":"33","author":"Park","year":"2016","journal-title":"Molecular Biology and Evolution"},{"key":"2026010712065337700_bib26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/jpi.12240","article-title":"Experimental and clinical aspects of melatonin and clock genes in diabetes","volume":"59","author":"Peschke","year":"2015","journal-title":"Journal of Pineal Research"},{"key":"2026010712065337700_bib27","doi-asserted-by":"publisher","first-page":"415","DOI":"10.3109\/07420528.2012.667859","article-title":"The endogenous melatonin (MT) signal facilitates reentrainment of the circadian system to light-induced phase advances by acting upon MT2 receptors","volume":"29","author":"Pfeffer","year":"2012","journal-title":"Chronobiology International"},{"key":"2026010712065337700_bib28","doi-asserted-by":"publisher","first-page":"1428","DOI":"10.1210\/me.2011-1355","article-title":"Research resource: genome-wide profiling of progesterone receptor binding in the mouse uterus","volume":"26","author":"Rubel","year":"2012","journal-title":"Molecular Endocrinology"},{"key":"2026010712065337700_bib29","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1210\/en.2015-1618","article-title":"Excess maternal fructose consumption increases fetal loss and impairs endometrial decidualization in mice","volume":"157","author":"Saben","year":"2016","journal-title":"Endocrinology"},{"key":"2026010712065337700_bib30","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12520","article-title":"Melatonin modulates autophagy and inflammation protecting human placental trophoblast from hypoxia\/reoxygenation","volume":"65","author":"Sagrillo-Fagundes","year":"2018","journal-title":"Journal of Pineal Research"},{"key":"2026010712065337700_bib31","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1111\/j.1600-079X.2004.00207.x","article-title":"Melatonin-estrogen interactions in breast cancer","volume":"38","author":"Sanchez-Barcelo","year":"2005","journal-title":"Journal of Pineal Research"},{"key":"2026010712065337700_bib32","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1093\/abbs\/gmz146","article-title":"Regulatory mechanisms of endometrial decidualization and pregnancy-related diseases","volume":"52","author":"Sang","year":"2020","journal-title":"Acta Biochimica et Biophysica Sinica"},{"key":"2026010712065337700_bib33","doi-asserted-by":"publisher","first-page":"2334","DOI":"10.1210\/me.2007-0058","article-title":"Transcriptional cross talk between the forkhead transcription factor forkhead box O1A and the progesterone receptor coordinates cell cycle regulation and differentiation in human endometrial stromal cells","volume":"21","author":"Takano","year":"2007","journal-title":"Molecular Endocrinology"},{"key":"2026010712065337700_bib34","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/j.reprotox.2008.03.005","article-title":"Melatonin and pregnancy in the human","volume":"25","author":"Tamura","year":"2008","journal-title":"Reproductive Toxicology"},{"key":"2026010712065337700_bib35","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/1757-2215-5-5","article-title":"The role of melatonin as an antioxidant in the follicle","volume":"5","author":"Tamura","year":"2012","journal-title":"Journal of Ovarian Research"},{"key":"2026010712065337700_bib36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/jog.12177","article-title":"Melatonin and female reproduction","volume":"40","author":"Tamura","year":"2014","journal-title":"Journal of Obstetrics and Gynaecology Research"},{"key":"2026010712065337700_bib37","doi-asserted-by":"publisher","first-page":"5270","DOI":"10.1074\/jbc.RA117.000234","article-title":"The distal upstream region of insulin-like growth factor\u2013binding protein-1 enhances its expression in endometrial stromal cells during decidualization","volume":"293","author":"Tamura","year":"2018","journal-title":"Journal of Biological Chemistry"},{"key":"2026010712065337700_bib38","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1007\/s00441-002-0581-4","article-title":"Mammalian melatonin receptors: molecular biology and signal transduction","volume":"309","author":"von Gall","year":"2002","journal-title":"Cell and Tissue Research"},{"key":"2026010712065337700_bib39","doi-asserted-by":"publisher","first-page":"1686","DOI":"10.1016\/j.fertnstert.2008.02.121","article-title":"Reduced expression of biomarkers associated with the implantation window in women with endometriosis","volume":"91","author":"Wei","year":"2009","journal-title":"Fertility and Sterility"},{"key":"2026010712065337700_bib40","doi-asserted-by":"publisher","first-page":"4789","DOI":"10.1210\/jcem.86.10.7912","article-title":"Direct action of melatonin in human granulosa-luteal cells","volume":"86","author":"Woo","year":"2001","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"2026010712065337700_bib41","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12839","article-title":"Pleiotropic roles of melatonin in endometriosis, recurrent spontaneous abortion, and polycystic ovary syndrome","volume":"80","author":"Yang","year":"2018","journal-title":"American Journal of Reproductive Immunology"},{"key":"2026010712065337700_bib42","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1177\/1933719117737843","article-title":"Increased expression of NDRG3 in mouse uterus during embryo implantation and in mouse endometrial stromal cells during in vitro decidualization","volume":"25","author":"Yang","year":"2018","journal-title":"Reproductive Sciences"},{"key":"2026010712065337700_bib43","doi-asserted-by":"publisher","first-page":"6170936","DOI":"10.1155\/2019\/6170936","article-title":"HB-EGF ameliorates oxidative stress-mediated uterine decidualization damage","volume":"2019","author":"Yu","year":"2019","journal-title":"Oxidative Medicine and Cellular Longevity"},{"key":"2026010712065337700_bib44","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-19-0284","article-title":"Circadian gene PER1 senses progesterone signal during human endometrial decidualization","author":"Zhang","year":"2019","journal-title":"Journal of Endocrinology 243 229- 242"},{"key":"2026010712065337700_bib45","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1034\/j.1600-079x.2002.02898.x","article-title":"Variations of mt1 melatonin receptor density in the rat uterus during decidualization, the estrous cycle and in response to exogenous steroid treatment","volume":"33","author":"Zhao","year":"2002","journal-title":"Journal of Pineal Research"},{"key":"2026010712065337700_bib46","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1093\/abbs\/gmz078","article-title":"Activation of Rev-erb\u03b1 attenuates lipopolysaccharide-induced inflammatory reactions in human endometrial stroma cells via suppressing TLR4-regulated NF-\u03baB activation","volume":"51","author":"Zhao","year":"2019","journal-title":"Acta Biochimica et Biophysica Sinica"}],"container-title":["Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rep.bioscientifica.com\/view\/journals\/rep\/162\/2\/REP-21-0159.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/reproduction\/article-pdf\/162\/2\/161\/64063471\/rep-21-0159.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/reproduction\/article-pdf\/162\/2\/161\/64063471\/rep-21-0159.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T17:07:10Z","timestamp":1767805630000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/reproduction\/article\/162\/2\/161\/8216937"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,12]]},"references-count":46,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,8,1]]}},"URL":"https:\/\/doi.org\/10.1530\/rep-21-0159","relation":{},"ISSN":["1470-1626","1741-7899"],"issn-type":[{"value":"1470-1626","type":"print"},{"value":"1741-7899","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,8,1]]},"published":{"date-parts":[[2021,7,12]]}}}