{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T22:13:43Z","timestamp":1793830423625,"version":"4.6.1"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T00:00:00Z","timestamp":1742947200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Science and Technology Assistance to Qinghai","award":["2022-QY-216"],"award-info":[{"award-number":["2022-QY-216"]}]},{"name":"Wuxi Municipal Health Commission Contract for Science and Technology Achievements and Promotion of Appropriate Technologies","award":["T202352"],"award-info":[{"award-number":["T202352"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,5,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>Recurrent spontaneous abortion (RSA) is associated with maternal-fetal interface dysfunction, particularly abnormal trophoblast invasion and proliferation. However, our understanding of the cause of RSA remains limited.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Plasma Trp and Kyn levels were measured in two groups using enzyme-linked immunosorbent assay. Immunofluorescence and western blot analyses were employed to evaluate the expression of IDO1, VEGFA, and proteins associated with epithelial-mesenchymal transition (EMT) in villous and decidual tissues from patients with RSA. The effects of Tryptophan (Trp) and IDO1-driven Trp-Kynurenine (Kyn) metabolism on trophoblast proliferation, migration, EMT, and angiogenesis were investigated in the HTR-8\/SVneo cell line using wound healing, transwell migration, quantitative real-time PCR (RT-qPCR), Western blotting, and tube formation assays. RNA sequencing (RNA-seq) identified differentially expressed genes in cells treated with 500\u00a0\u03bcM exogenous L-Trp.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>RSA patients exhibited elevated plasma Trp levels and significantly reduced Kyn levels, indicating decreased IDO1 activity (as assessed by the Kyn\/Trp ratio) compared to controls. IDO1, EMT-related proteins, and VEGFA were downregulated in RSA patient tissues. In vitro, L-Trp enhanced trophoblast migration, invasion, EMT, and microvasculature formation via IDO1 activation. The reduced functional capabilities induced by the IDO1 antagonist 1-MT (500\u00a0\u03bcM) were rescued by Kyn (300\u00a0\u03bcM). RNA-seq revealed that L-Trp upregulation modulates trophoblast gene expression and functional pathways associated with amino acid metabolism, angiogenesis, and vasculature development.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Discussion<\/jats:title>\n                  <jats:p>Our study reveals a novel molecular mechanism by which Trp metabolism regulates HTR-8 cell function, suggesting that modulating IDO1 activity may represent a therapeutic strategy to improve trophoblast function and pregnancy outcomes in RSA.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/biolre\/ioaf040","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T02:02:57Z","timestamp":1743386577000},"page":"969-980","source":"Crossref","is-referenced-by-count":7,"title":["Therapeutic targeting of the Tryptophan-Kynurenine Axis for HTR-8\/SVneo trophoblast proliferation and migration in unexplained recurrent spontaneous abortion"],"prefix":"10.1093","volume":"112","author":[{"given":"Pingping","family":"Jin","sequence":"first","affiliation":[{"name":"Affiliated Women\u2019s Hospital of Jiangnan University , Wuxi, Jiangsu ,","place":["China"]},{"name":"Wuxi School of Medicine, Jiangnan University , Wuxi, Jiangsu ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Lu","sequence":"additional","affiliation":[{"name":"Affiliated Women\u2019s Hospital of Jiangnan University , Wuxi, Jiangsu ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Wang","sequence":"additional","affiliation":[{"name":"Affiliated Women\u2019s Hospital of Jiangnan University , Wuxi, Jiangsu ,","place":["China"]},{"name":"Wuxi School of Medicine, Jiangnan University , Wuxi, Jiangsu ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Chen","sequence":"additional","affiliation":[{"name":"Affiliated Women\u2019s Hospital of Jiangnan University , Wuxi, Jiangsu ,","place":["China"]},{"name":"Wuxi School of Medicine, Jiangnan University , Wuxi, Jiangsu ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Yang","sequence":"additional","affiliation":[{"name":"Affiliated Women\u2019s Hospital of Jiangnan University , Wuxi, Jiangsu ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongxiang","family":"Yin","sequence":"additional","affiliation":[{"name":"Affiliated Women\u2019s Hospital of Jiangnan University , Wuxi, Jiangsu ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Shen","sequence":"additional","affiliation":[{"name":"Affiliated Women\u2019s Hospital of Jiangnan University , Wuxi, Jiangsu ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxin","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Huishan District People's Hospital , Wuxi, Jiangsu ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daozhen","family":"Chen","sequence":"additional","affiliation":[{"name":"Affiliated Women\u2019s Hospital of Jiangnan University , Wuxi, Jiangsu ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Affiliated Women\u2019s Hospital of Jiangnan University , Wuxi, Jiangsu ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Affiliated Women\u2019s Hospital of Jiangnan University , Wuxi, Jiangsu ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,3,26]]},"reference":[{"key":"2025052711542260000_ref1","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/s41572-020-00228-z","article-title":"Recurrent pregnancy loss","volume":"6","author":"Dimitriadis","year":"2020","journal-title":"Nat Rev Dis Primers"},{"key":"2025052711542260000_ref2","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1093\/humrep\/dey347","article-title":"The role of the PD-1\/PD-L1 Axis in macrophage differentiation and function during pregnancy","volume":"34","author":"Zhang","year":"2019","journal-title":"Hum Reprod"},{"key":"2025052711542260000_ref3","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1093\/humupd\/dmz048","article-title":"Recurrent pregnancy loss: diagnostic workup after two or three pregnancy losses? 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