Successful human pregnancy depends on the precise regulation of placental development, particularly the differentiation and functional activity of trophoblast cells (Knofler et al., 2019). Central to placental function are the chorionic villi, which mediate the essential exchange of nutrients, gases, and waste products between mother and fetus. Cytotrophoblasts (CTBs) proliferate and fuse to form syncytiotrophoblast (STBs), which form a specialized multinucleated layer. STBs support maternal-fetal exchange and produce key hormones for pregnancy maintenance (Valdez-Martinez and Bedolla, 2021). Maintaining metabolic homeostasis within this dynamic tissue, including the regulation of lactate production and transport, is fundamental for supporting the high energy demands and signaling requirements of the developing trophoblasts (Shen et al., 2024).

Lactate is both an energy substrate and signaling molecule influencing trophoblast function (Gardner, 2015, Gurner and Gardner, 2025). Under physiological conditions, placental lactate is tightly controlled, whereas impaired lactate transport is linked to miscarriage and preeclampsia (Li et al., 2025; Shen et al., 2024). Monocarboxylate transporter 1 (MCT1) facilitates lactate transport. While extensively studied in oncology for its role in cancer cell metabolism (Doherty et al., 2014) (Eichner et al., 2016, Erdem et al., 2022, Tasdogan et al., 2020), its physiological importance in the placenta requires further clarification. MCT1 is prominently expressed in the syncytiotrophoblast membranes of the human placenta, suggesting a potential involvement in the lactate flux essential for normal placental function (Nagai et al., 2010; Settle et al., 2004). However, the specific functional importance of MCT1 in early placental development, particularly STB differentiation and function, and the molecular consequences of its disruption, remain largely unexplored.

To address this, we investigated MCT1 in pregnancy maintenance. We hypothesized that MCT1 disruption impairs STB integrity and placental development, leading to miscarriage. Using human villi, mouse models, and BeWo cells, we provide functional evidence for the essential role of MCT1 and identify upstream transcriptional regulators crucial for trophoblast homeostasis.