{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T19:47:14Z","timestamp":1776714434114,"version":"3.51.2"},"reference-count":36,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>TGF\u03b21 plays a key role in placental development, but its regulation of trophoblast function isn't fully known. Meanwhile, the TLR4\/NF\u2010\u03baB pathway is linked to trophoblast dysfunction, yet the mediator linking TGF\u03b21 to this pathway is unclear. Thus, this study examines if tTG mediates TGF\u03b21's regulation of trophoblast functions via TLR4\/NF\u2010\u03baB and its relevance in preeclampsia (PE). To address this, HTR\u20108\/Svneo cells were treated with TGF\u03b21, cell migration, invasion, and proliferation were assessed via Transwell and CCK\u20108 assays. The expression of tTG, TLR4\/NF\u2010\u03baB pathway components, and pro\u2010inflammatory cytokines was evaluated by qPCR and Western blot. Gain\u2010 and loss\u2010of\u2010function approaches for tTG and TLR4 were employed, alongside transcriptome sequencing. The role of tTG's enzymatic activity was tested using the inhibitor Z\u2010DON. Placental tissues from normal and preeclamptic pregnancies were analyzed for clinical validation. The results showed that TGF\u03b21 dose\u2010dependently inhibited trophoblast migration, invasion, and proliferation while upregulating tTG expression. tTG overexpression activated the TLR4\/NF\u2010\u03baB pathway and altered the transcriptome. TLR4 inhibition blocked tTG\u2010mediated NF\u2010\u03baB activation. Furthermore, tTG knockdown and inhibiting tTG's enzymatic activity reversed the suppressive effects of TGF\u03b21 on cell functions and downstream TLR4\/NF\u2010\u03baB signaling. Clinically, the protein levels of tTG and activated TLR4\/NF\u2010\u03baB pathway components were significantly elevated in preeclamptic placentas. In conclusion, this study first reveals a TGF\u03b21\/tTG\/TLR4\/NF\u2010\u03baB axis in trophoblasts, showing TGF\u03b21 inhibits trophoblast function via upregulation of tTG, which functionally leads to activation of the TLR4\/NF\u2010\u03baB pathway in an enzyme activity\u2010dependent manner, providing new insights into PE pathogenesis and potential therapeutic targets.<\/jats:p>","DOI":"10.1002\/jbt.70844","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T19:14:55Z","timestamp":1776712495000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TGF\u03b21 Inhibits Migration, Invasion, and Proliferation of HTR\u20108\/Svneo Cells via tTG\u2010Activated TLR4\/NF\u2010\u03baB Signaling Pathway"],"prefix":"10.1002","volume":"40","author":[{"given":"Mi","family":"Cheng","sequence":"first","affiliation":[{"name":"Jinan University Guangdong Guangzhou China"},{"name":"Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health Guangzhou Medical University Guangdong Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaodan","family":"Di","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health Guangzhou Medical University Guangdong Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiaozhu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health Guangzhou Medical University Guangdong Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taowei","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health Guangzhou Medical University Guangdong Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health Guangzhou Medical University Guangdong Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4283-6394","authenticated-orcid":false,"given":"Huiqian","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health Guangzhou Medical University Guangdong Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanqin","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health Guangzhou Medical University Guangdong Guangzhou China"},{"name":"Institute of Reproductive Health and Perinatology, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangdong Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zequn","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health Guangzhou Medical University Guangdong Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kun","family":"Shi","sequence":"additional","affiliation":[{"name":"Jinan University Guangdong Guangzhou China"},{"name":"Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health Guangzhou Medical University Guangdong Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.placenta.2023.03.005","article-title":"Transcriptomic Profiling in Hypoxia\u2010Induced Trophoblast Cells for Preeclampsia","volume":"136","author":"Liu Z.","year":"2023","journal-title":"Placenta"},{"issue":"1","key":"e_1_2_12_3_1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s13619-025-00261-x","article-title":"Transient Inhibition of MEK\/ERK and Wnt Pathways Enhances Direct Differentiation of Primed hPSCs Into Functional Trophoblast Stem Cells","volume":"15","author":"Jiang 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