{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T00:53:11Z","timestamp":1773449591070,"version":"3.50.1"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81370735 81771610"],"award-info":[{"award-number":["81370735 81771610"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>We investigated the role of neural Wiskott-Aldrich syndrome protein (N-WASP) in preeclampsia (PE), focusing on its regulatory impact on trophoblast syncytialization.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed placental samples from patients with PE (n = 30) and controls (n = 35) using RNA extraction, quantitative real-time polymerase chain reaction, Western blot, and immunohistochemistry. BeWo cell lines were used to model trophoblast fusion under forskolin stimulation. We explored N-WASP\u2019s role in trophoblast cell behavior using gene knockdown and overexpression experiments. Using bioinformatics analyses and molecular docking studies, we elucidated the interaction between N-WASP and associated pathways. These findings were validated\n                      <jats:italic>in vivo<\/jats:italic>\n                      using an L-NAME PE rat model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      N-WASP expression was significantly reduced in PE placentas, correlating positively with syncytin-2 and GCM1 levels. In BeWo cells, N-WASP promoted syncytialization by activating the FAK\/\u03b2-catenin pathway, causing increased nuclear \u03b2-catenin translocation, glial cells missing 1 expression, and syncytin-2 transcription. Mechanistically, N-WASP interacted with myosin 1B causing FAK pathway activation. Restoring N-WASP expression ameliorated placental abnormalities and PE symptoms\n                      <jats:italic>in vivo<\/jats:italic>\n                      . We identified hydroxychloroquine as a potential N-WASP agonist, capable of enhancing trophoblast syncytialization\n                      <jats:italic>in vitro<\/jats:italic>\n                      using molecular docking. Treatment with hydroxychloroquine significantly improved clinical symptoms, including reducing elevated blood pressure, decreasing urinary protein levels, and normalizing serum creatinine concentrations in PE rat models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We identified N-WASP as a key regulator of trophoblast syncytialization through the FAK\/\u03b2-catenin signaling pathway, influencing syncytin-2 expression. The findings reveal a novel molecular mechanism underlying PE and suggest that N-WASP is a potential therapeutic target for PE.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2025.1678878","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T07:04:05Z","timestamp":1762412645000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Reduced Wiskott-Aldrich syndrome protein expression in preeclampsia placenta impairs trophoblast syncytialization by modulating syncytin-2 via FAK\/\u03b2-catenin pathway"],"prefix":"10.3389","volume":"13","author":[{"given":"Shuo","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunpeng","family":"Ge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pin","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zekai","family":"Bai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongfei","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chong","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"W530","DOI":"10.1093\/nar\/gkab294","article-title":"PLIP 2021: expanding the scope of the protein-ligand interaction profiler to DNA and RNA","volume":"49","author":"Adasme","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1080\/21541248.2017.1390522","article-title":"Crosstalk between WIP and Rho family GTPases","volume":"11","author":"Ant\u00f3n","year":"2020","journal-title":"Small GTPases"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2837","DOI":"10.3390\/ijms20112837","article-title":"The role of epigenetics in placental development and the etiology of preeclampsia","volume":"20","author":"Apicella","year":"2019","journal-title":"Int. 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