Antiferroptotic Drugs Reduce sFlt-1 Release and Placenta Damage in Preeclampsia
Sapir Lianski, Tehila Mizrachi, Oren Barak, Lilah Tsaitlin-Mor, Shirin Elhaik-Goldman, S. Yagel, Debra Goldman‐Wohl, S. M. Cohen, R Medina, Jacob Rachmilewitz, Haim Barr, A.N. Plotnikov, Yulia Y. Tyurina, Vladimir A. Tyurin, Svetlana N. Samovich, Alexandr A. Kapralov, S. Ananth Karumanchi, Valerian E. Kagan, Hülya Bayır, Yoel Sadovsky, Ofer Beharier
Abstract
BACKGROUND: Preeclampsia is characterized by hypertension, proteinuria, and elevated antiangiogenic sFlt-1 (soluble fms-like tyrosine kinase-1) levels. Despite extensive research, mechanisms underlying sFlt-1 dysregulation remain unclear. This hypothesis-testing study investigated whether ferroptosis, a lipid peroxidation-driven cell death mechanism, contributes to preeclamptic placental pathogenesis and sFlt-1 release, and whether drug repurposing could identify novel therapeutic options. METHODS: We analyzed oxidized phosphatidylethanolamines in human preeclamptic and healthy placental tissues using redox phospholipidomics. In placental explants, we evaluated ferroptosis effects on sFlt-1 release using Ferrostatin-1 and deferoxamine as inhibitors. We screened 6520 drugs and compounds to identify effective ferroptosis inhibitors in primary trophoblasts. Statistical analyses used Student t test and 1-way ANOVA with multiple comparison corrections. RESULTS: Preeclamptic placentas showed significant accumulation of oxidized phosphatidylethanolamines compared with controls. Inducing ferroptosis in placental explants increased sFlt-1 release, while inhibition using Ferrostatin-1 and deferoxamine reduced sFlt-1 levels ( P <0.01). Our screen identified dipyridamole and promethazine as potent ferroptosis inhibitors, reducing lipid peroxidation, preserving glutathione levels, and decreasing sFlt-1 release in preeclamptic explants. CONCLUSIONS: This study establishes placental ferroptosis as a key mechanism in early preeclampsia and demonstrates its direct link to sFlt-1 dysregulation. Our systematic drug screening approach identified approved drugs with antiferroptotic activity, suggesting a novel therapeutic strategy for preeclampsia management through drug repurposing. Further research is needed to establish optimal dosing and confirm efficacy in vivo.