PFKFB4 downregulation impairs decidualization via disturbing the glycolysis and GSK3β/β-catenin pathway and contributes to preeclampsia.

Preeclampsia (PE), a pregnancy-specific complication threatening maternal and fetal health, has an elusive pathogenesis. While placental dysplasia is a core driver, decidualization is essential for placentation. Our prior RNA sequencing identified significant downregulation of the key glycolytic enzyme PFKFB4 in decidual tissue from severe PE (sPE) patients. Here, we confirmed markedly lower PFKFB4 expression in sPE decidual tissue than in normal pregnant (NP) women. In in vitro artificial decidualization models, PFKFB4 expression increased significantly with decidualization progression, and siRNA-mediated PFKFB4 knockdown strongly impaired this process. Reducing glucose consumption, lactate production, cell proliferation, and migration. Co-immunoprecipitation (Co-IP) experiments showed that PFKFB4 interacts with GSK3β; PFKFB4 knockdown inhibited the GSK3β/β-catenin pathway, which, on the one hand, further suppressed glycolysis by downregulating LDHA and inducing cellular energy depletion, and on the other hand, decreased the expression of proliferation-related genes, thereby inhibiting cell proliferation and migration at energy metabolism and gene expression levels, and ultimately leading to decidualization defects. In summary, PFKFB4 is a dual regulator of aerobic glycolysis and the GSK3β/β-catenin pathway in decidualization; its downregulation in sPE impairs decidualization, potentially reducing trophoblast invasion and triggering placental dysplasia, highlighting PFKFB4 as a potential PE biomarker and therapeutic target.