Reduced Wiskott-Aldrich syndrome protein expression in preeclampsia placenta impairs trophoblast syncytialization by modulating syncytin-2 via FAK/β-catenin pathway.

Objective: We investigated the role of neural Wiskott-Aldrich syndrome protein (N-WASP) in preeclampsia (PE), focusing on its regulatory impact on trophoblast syncytialization. Methods: 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's 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 Results: 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/β-catenin pathway, causing increased nuclear β-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 Conclusion: We identified N-WASP as a key regulator of trophoblast syncytialization through the FAK/β-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.