{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T19:27:37Z","timestamp":1778873257674,"version":"3.51.4"},"reference-count":35,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Reproduction Devel"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Endometriosis is hypothesized to result from retrograde menstruation where cell debris including endometrial stromal cells (ESCs) travel through the fallopian tubes. This chronic inflammatory disease is characterized by inflammatory and fibrotic endometrial tissue. We have previously observed reduced expression of the anti\u2010inflammatory factor SERPINA1 in endometriosis\u2010like lesions in a mouse model implanted with human ESCs. Additionally, pro\u2010inflammatory factors present in peritoneal hemorrhage exacerbated inflammation in these grafts, partly through prostaglandin (PG) E2 and thrombin. However, it remains unclear whether the reduction of SERPINA1, in combination with PGE2 and thrombin, synergistically influences the expression of inflammatory factors in endometriosis lesions and the underlying mechanisms. We analyzed RNA sequencing data from ESCs treated with SERPINA1 siRNA and PGE2\/thrombin, comparing them to data sets derived from ESCs subjected to either SERPINA1 knockdown or PGE2\/thrombin treatment. Comparative analysis identified 49 transcripts that were upregulated under both conditions and enriched for transcription regulatory genes, including SNAI1, HDAC5, PBX1, SOX4, EPAS1, LHX9, and MAFK. Silencing SNAI1, HDAC5, SOX4, EPAS1, or LHX9 suppressed IL6, CXCL8, and IL1B expression, which had been upregulated by SERPINA1 siRNA and PGE2\/thrombin. Among these genes, LHX9 expression was significantly elevated in ectopic lesions, predominantly localized to stromal and glandular epithelial cells, with more pronounced expression during the secretory phase. LHX9 levels were also increased in endometriotic lesions compared to the normal endometrium. In conclusion, reduced SERPINA1 expression in ectopic ESCs, combined with PGE2\/thrombin, induces inflammatory cytokine expression linked to LHX9. Pharmacological targeting of LHX9 may present a promising therapeutic strategy for mitigating chronic inflammation in endometriotic lesions.<\/jats:p>","DOI":"10.1002\/mrd.70046","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T18:33:51Z","timestamp":1755110031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Role of Transcription Factor, LIM Homeobox 9 (LHX9) in Inflammatory Response by PGE2 and Thrombin in SERPINA1\u2010Silencing Endometrial Stromal Cells"],"prefix":"10.1002","volume":"92","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9120-0475","authenticated-orcid":false,"given":"Kazuya","family":"Kusama","sequence":"first","affiliation":[{"name":"Department of Endocrine Pharmacology Tokyo University of Pharmacy and Life Sciences Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Misuzu","family":"Ashihara","sequence":"additional","affiliation":[{"name":"Department of Endocrine Pharmacology Tokyo University of Pharmacy and Life Sciences Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moana","family":"Okita","sequence":"additional","affiliation":[{"name":"Department of Endocrine Pharmacology Tokyo University of Pharmacy and Life Sciences Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kanoko","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Endocrine Pharmacology Tokyo University of Pharmacy and Life Sciences Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masumi","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Endocrine Pharmacology Tokyo University of Pharmacy and Life Sciences Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaito","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Endocrine Pharmacology Tokyo University of Pharmacy and Life Sciences Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rena","family":"Hosokawa","sequence":"additional","affiliation":[{"name":"Department of Endocrine Pharmacology Tokyo University of Pharmacy and Life Sciences Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikihiro","family":"Yoshie","sequence":"additional","affiliation":[{"name":"Department of Endocrine Pharmacology Tokyo University of Pharmacy and Life Sciences Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junya","family":"Kojima","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Tokyo Medical University Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yumi","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Saitama Medical University Saitama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masanori","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Tokyo Medical University Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirotaka","family":"Nishi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Tokyo Medical University Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Kajihara","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Saitama Medical University Saitama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiro","family":"Tamura","sequence":"additional","affiliation":[{"name":"Department of Endocrine Pharmacology Tokyo University of Pharmacy and Life Sciences Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,8,13]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/15.4.767"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrep.2021.100967"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/der253"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/35002622"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2018-00242"},{"issue":"1","key":"e_1_2_9_7_1","first-page":"48","article-title":"Prostaglandin F2 Alpha and E2 Release by Peritoneum With and Without Endometriosis","volume":"33","author":"De Leon F. D.","year":"1988","journal-title":"International Journal of Fertility"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(04)17403-5"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.16342"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1530\/REP-15-0555"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1309648110"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiu620"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqab207"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gaab036"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.966455"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2021.07.075"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1177\/1933719115602768"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2010.11.039"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2004.10.058"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deu123"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2010.08.006"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1254\/jphs.08r13fm"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejogrb.2007.05.001"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0208145"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmr030"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1254\/jphs.11216fp"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12622"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1159\/000518323"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1177\/1933719115570901"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dex354"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.16472"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22073683"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23041955"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2016.03.015"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.00612"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-018-0008-5"}],"container-title":["Molecular Reproduction and Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mrd.70046","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T05:28:34Z","timestamp":1756358914000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mrd.70046"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8]]},"references-count":35,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1002\/mrd.70046"],"URL":"https:\/\/doi.org\/10.1002\/mrd.70046","archive":["Portico"],"relation":{},"ISSN":["1040-452X","1098-2795"],"issn-type":[{"value":"1040-452X","type":"print"},{"value":"1098-2795","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8]]},"assertion":[{"value":"2025-01-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70046"}}