Integrative transcriptomic analysis and preclinical validation identify lansoprazole as a therapeutic candidate for preeclampsia

Abstract

Preeclampsia is a pregnancy disorder with often severe consequences across the maternal-fetal dyad and limited treatment options. We performed an integrated meta-analysis of six placental transcriptomic datasets to identify a preeclampsia-specific gene expression signature, revealing dysregulated pathways related to hypoxia, immune dysfunction, and metabolism. Multivariate INTegrative (MINT) analysis was used to establish a smaller predictive signature with potential utility for identifying circulating biomarkers for earlier preeclampsia diagnosis and monitoring disease progression. This preeclampsia signature queried against a transcriptomic database of more than 1,000 compounds identified lansoprazole, a widely used proton pump inhibitor with an established safety profile, as the top-ranked compound based on its ability to reverse the preeclampsia-associated gene expression signature. Protective benefits of lansoprazole were confirmed using a murine model of immune-mediated fetal wastage where treatment overturned elevated soluble FLT1 levels with significantly improved pregnancy outcomes. These findings support further investigation of lansoprazole as a potential therapy for preeclampsia.