Paeonol improves preeclampsia by inhibiting ferroptosis by regulating ACSL4 protein ubiquitination

This study aimed to investigate the effects of paeonol (pae) on blood pressure, tissue damage, and the fetuses and placentas in a preeclampsia (PE) rat model induced by L-NAME, and to explore the potential regulatory mechanism involving the NEDD4L-ACSL4 axis. By quantitatively analyzing urinary protein, blood pressure, and sFlt-1 levels, the role of pae in the PE rat model was evaluated. The effects of pae on HTR-8/SVneo and primary trophoblast cells were investigated using a cell model. The role of pae in the process of NEDD4L-mediated ACSL4 ubiquitination was determined through experiments such as Co-IP and ubiquitination assays. Pae reduced blood pressure, urinary protein, and sFlt-1 levels in a PE rat model, increased the fetal survival rate, and improved placental and renal damage. Mechanistically, pae mediated the ubiquitination level of ACSL4 by promoting the interaction between ACSL4 and NEDD4L, thereby reversing hypoxia-induced ferroptosis. In brief, pae further inhibited ferroptosis by facilitating NEDD4L-mediated ACSL4 ubiquitination, exerting a significant improving effect on blood pressure and tissue damage in PE. Thus, it provided a new strategy for the treatment of PE and laid a foundation for further research on the mechanism of action of pae and its related compounds.