LAT1-NRF2 axis controls sFlt-1/PlGF imbalance and oxidative stress in preeclampsia

Sebastian Granitzer, Raimund Widhalm, Isabella Ellinger, Harald Zeisler, Martin Forsthuber, Philipp Foessleitner, Elisabeth Geschrey, Leila Saleh, Martin Knöfler, Gernot Desoye, Paul Ettel, Thomas Weichhart, Laszlo Musiejovsky, Gernot Schabbauer, Hans Salzer, Margit Rosner, Markus Hengstschläger and Claudia Gundacker ()
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Sebastian Granitzer: Karl-Landsteiner Private University for Health Sciences
Raimund Widhalm: Karl-Landsteiner Private University for Health Sciences
Isabella Ellinger: Medical University of Vienna
Harald Zeisler: Medical University of Vienna
Martin Forsthuber: Medical University of Vienna
Philipp Foessleitner: Medical University of Vienna
Elisabeth Geschrey: University Hospital St. Pölten
Leila Saleh: Medical University of Vienna
Martin Knöfler: Medical University of Vienna
Gernot Desoye: Medical University of Graz
Paul Ettel: Medical University of Vienna
Thomas Weichhart: Medical University of Vienna
Laszlo Musiejovsky: Medical University Vienna
Gernot Schabbauer: Medical University Vienna
Hans Salzer: University Clinic Tulln
Margit Rosner: Medical University of Vienna
Markus Hengstschläger: Medical University of Vienna
Claudia Gundacker: Medical University of Vienna

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Preeclampsia (PE) is a complex disease with unclear etiology. It is the most dangerous human pregnancy disease, causing morbidity and mortality in thousands of women and newborns worldwide. The soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) ratio is currently the best and only predictive biomarker. The higher the ratio, the more likely the pregnant women will develop PE. The molecular mechanism underlying the increased sFlt-1/PlGF ratio is not known. Here, we show that amino acid transporter LAT1 (SLC7A5) and transcription factor NRF2 regulate this ratio via a previously unknown mechanism to produce sFlt-1 and PlGF in an anti-angiogenic ratio as observed in PE. In addition, we show that PE-associated oxidative stress, whose origin was unknown, is a secondary phenomenon caused by reduced NRF2 and LAT1 activity. The interdependence of the involved proteins, including also ATF4, Flt-1 and Akt, indicates that any disruption of the interaction would ultimately lead to a PE-like phenotype.

Date: 2025
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DOI: 10.1038/s41467-025-64160-0

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