PDK1 downregulation impairs decidualization via dysregulated glycolysis: Potential relevance to preeclampsia

Preeclampsia (PE) is a pregnancy-specific syndrome affecting over 8 million mother-infant pairs annually; while most prior studies on PE pathogenesis have focused on the placenta, decidualization is fundamental to placentation and subsequent pregnancy progression. Pyruvate dehydrogenase kinase-1 (PDK1) is a key regulator of metabolic switching, as it promotes glycolysis and inhibits oxidative phosphorylation. Although PDK1 is aberrantly upregulated in various tumors, its role in PE remains unclear. In this study, we first observed that PDK1 expression in decidual tissues was significantly lower in patients with severe PE than in normal pregnant women. In vitro, PDK1 expression increased significantly during the decidualization of human endometrial stromal cells, accompanied by upregulated mRNA levels of aerobic glycolysis-related genes (LDHA and MCT4) and downregulated expression of the oxidative phosphorylation enzyme IDH2. Moreover, PDK1 knockdown impaired decidualization, significantly reduced LDHA and MCT4 expression, increased IDH2 levels, suppressed glucose uptake and lactate production, and inhibited trophoblast invasion. In vivo experiments in mice further confirmed that PDK1 expression increases with decidual progression during both normal pregnancy and pseudopregnancy, which is paralleled by enhanced glycolysis and reduced oxidative phosphorylation. Collectively, these findings indicate that PDK1 plays a critical role in decidualization through promoting glycolysis and inhibiting oxidative phosphorylation, with aberrant PDK1 expression potentially impairing decidualization and being associated with PE pathogenesis.