Antiferroptotic Drugs Reduce sFlt-1 Release and Placenta Damage in Preeclampsia

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 FDA-approved drugs (pregnancy categories A-C) 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.