Ultrasound-targeted delivery of miR-513a-5p inhibits ferroptosis and restores vascular function in preeclampsia.

Preeclampsia (PE) is a hypertensive pregnancy disorder with limited therapeutic options. This study explores the role of miR-513a-5p in modulating ferroptosis via TXNIP and evaluates its therapeutic delivery using ultrasound-targeted microbubble destruction (UTMD). miR-513a-5p was identified as significantly downregulated in PE through GEO analysis (GSE84260). To assess its function, miR-513a-5p was overexpressed in HTR-8/SVneo and TEV-1 trophoblast cells, and its effects on proliferation, apoptosis, migration, and ferroptosis were evaluated. TXNIP was investigated as a mechanistic target using dual-luciferase and RNA pulldown assays, and its functional relevance was tested via rescue experiments. To assess translational applicability, miR-513a-5p was delivered using UTMD both in vitro and via tail vein injection in a rat model of PE. On gestational day (GD) 19, blood pressure, urinary protein, and fetal survival were assessed. On GD22, oxidative stress markers such as reactive oxygen species (ROS), malondialdehyde (MDA), Fe2+, glutathione (GSH), superoxide dismutase (SOD), ferroptosis regulators (GPX4, SLC7A11), and angiogenic factors (sFlt-1, PlGF, VEGF) were measured. Bioinformatics analysis revealed miR-513a-5p as one of the significantly downregulated miRNAs in PE which was validated in placental tissues. miR-513a-5p overexpression promoted trophoblast proliferation, migration, and EMT, and reduced apoptosis and ferroptosis in trophoblast cells. TXNIP was validated as a direct target of miR-513a-5p, and its reintroduction reversed the protective effects of miR-513a-5p. UTMD enhanced miR-513a-5p delivery in vitro compared to lipofection and improved trophoblast viability and function. In vivo, administration of UTMD-mediated miR-513a-5p delivery reduced blood pressure, proteinuria, and oxidative stress, and improved fetal survival, antioxidant levels, and vascular markers. UTMD enhanced miR-513a-5p delivery in vitro and promoted trophoblast function.