WTAP Dysregulation Mediates HLF‐m6A Modification to Inhibit Trophoblast Ferroptosis in Preeclampsia

Preeclampsia (PE) is a severe pregnancy-specific disorder that poses significant risks to maternal and perinatal health. The pathophysiological mechanisms underlying PE are complex and not yet fully elucidated. This study focuses on the role of ferroptosis in PE and identifies a significant downregulation of the transcription factor hepatic leukemia factor (HLF) in PE placental tissues. Further investigations reveal that HLF transcriptionally activates solute carrier family 7 member 11 (SLC7A11) to inhibit trophoblast ferroptosis, thereby maintaining their proliferation, migration, and invasion functions. Additionally, Wilms' tumor 1-associating protein (WTAP), a key factor in N6-methyladenosine (m6A) methylation, regulates HLF mRNA stability in an m6A-dependent manner, influencing the expression of its downstream target SLC7A11. This study, for the first time, systematically clarifies the critical role of the WTAP/HLF/SLC7A11 signaling axis in the pathogenesis of PE from the perspective of ferroptosis. The findings offer a novel theoretical basis for further exploration of the molecular mechanisms of PE and potential intervention targets for precision therapy.