Resveratrol Activates SIRT1 to Inhibit Trophoblast Pyroptosis in Preeclampsia

Preeclampsia (PE) is a hypertensive disorder of severe pregnancy complication characterized by placental dysfunction and systemic inflammation. Resveratrol (RES), a natural polyphenol, has been shown to exert anti-inflammatory effects partly through the activation of SIRT1. NLRP3 inflammasome-mediated pyroptosis plays a crucial role in placental inflammation. This study aims to investigate the role of RES in regulating trophoblast pyroptosis through SIRT1 activation in PE. Placental tissues from PE patients and normal pregnancies were analyzed for SIRT1 and pyroptosis markers. A lipopolysaccharide (LPS)-induced PE mouse model and HTR-8/SVneo trophoblasts model were used to examine for pyroptosis following RES treatment. Placental tissues from PE patients exhibited significantly reduced SIRT1 expression and elevated pyroptosis markers (NLRP3, Caspase-1) compared to normal pregnancies. In a LPS-induced PE mouse model, RES treatment ameliorated pregnancy outcomes by reducing blood pressure, proteinuria, and improving renal morphology. RES also enhanced fetal and placental development, as evidenced by decreased embryo resorption rates, increased fetal weight, and improved spiral artery remodeling. Mechanistically, RES upregulated SIRT1 expression and suppressed pyroptosis-related proteins (NLRP3, Caspase-1, GSDMD, ASC) in placental tissues of PE mice. In vitro, RES attenuated LPS-induced trophoblast dysfunction by enhancing proliferation, migration, and invasion in HTR-8/SVneo cells. This was accompanied by SIRT1-mediated suppression of pyroptosis and reduced secretion of inflammatory cytokines (IL-18, IL-1β). These findings demonstrate that RES activates SIRT1 to inhibit trophoblast pyroptosis, thereby improving placental function and pregnancy outcomes in PE. This study highlights RES as a potential therapeutic agent for PE by modulating SIRT1-mediated pyroptosis pathways.