Lactate shuttle between cytotrophoblast and syncytiotrophoblast in the placenta enhances ferroptosis resistance and maintains placental homeostasis: implications for early pregnancy loss

The placenta serves as the interface between the mother and fetus, playing a critical role in ensuring fetal development and maternal health during pregnancy in viviparous mammals. In human placental villi, the outermost multinucleated syncytiotrophoblast (STB) are formed through the syncytialization of inner layer mononucleated cytotrophoblasts (CTBs). Despite the high cellular homeostasis exhibited by STB, the underlying mechanisms remain poorly understood. Our recent investigation into the metabolic properties of human placental trophoblasts reveals significant metabolic rewiring during syncytialization. This leads us to hypothesize that lactate produced by CTBs may be actively transported to STB, potentially protecting polyunsaturated fatty acids (PUFA)-rich STB from excessive ferroptosis, thereby contributing to the maintenance of cellular homeostasis in STB. To test this hypothesis, we conducted both in vitro and in vivo studies, utilizing clinical specimens from patients with recurrent pregnancy loss (RPL), primary cultured human CTBs and STB, induced syncytialization of trophoblast cell line BeWo, and a lipopolysaccharide (LPS)-induced mouse model of early pregnancy loss. Our data demonstrates that lactate primarily produced by CTBs can be transported to STB via monocarboxylate transporter 1 (MCT1)-mediated transport, activating the PI3K (phosphatidylinositol 3-kinase)-AKT (protein kinase B, PKB)-mTOR (mechanistic target of rapamycin) signaling pathway, and subsequently upregulating the expression of stearoyl-CoA desaturase-1 (SCD1) and glutathione peroxidase 4 (GPX4). This process mitigates lipid peroxidation and reduces ferroptosis susceptibility in STB. Administration of lactate in LPS-induced mice significantly mitigates placental ferroptosis and rescues fetal loss. Pathological analyses of the placentas from RPL (recurrent early pregnancy loss) patients demonstrates impaired lactate synthesis capacity and elevated ferroptosis biomarkers. These findings elucidate the mechanism whereby lactate shuttle between trophoblast layers suppresses ferroptosis and maintains cellular homeostasis in the placenta. The results highlight the potential therapeutic utility of lactate for addressing severe pregnancy complications such as early pregnancy loss. RPL, typically characterized by three or more consecutive spontaneous pregnancy loss before 24 weeks of gestational age, imposes profound physical and psychological burdens on affected women. Despite advances in assisted reproductive technologies (ART), IVF/ICSI cycles often fail to improve live birth rates in RPL patients, as studies show no significant reduction in miscarriage rates even with embryo selection or hormonal support. The clinical dilemma stems from over 50% of RPL cases remaining idiopathic after exhaustive evaluations, leaving limited evidence-based therapeutic options such as progesterone supplementation or immunomodulation with inconsistent efficacy. Emerging evidence highlights placental villi dysfunction as a pivotal contributor to RPL pathogenesis, and underscores targeting placental resilience pathways as promising therapeutic avenues to break the cycle of recurrent losses. Our findings uncover the mechanism by which placental STB maintain cellular homeostasis through metabolic crosstalk with CTBs. The intricate regulation of cellular homeostasis is essential for in utero fetal development. We find that impaired lactate production and transportation in the placenta from human RPL patients are strongly associated with excessive ferroptosis and fetal mortality. In a mouse model with early pregnancy loss, appropriate lactate supplementation significantly improves fetal survival rate. These findings underscore the potential therapeutic utility of this metabolite for addressing severe pregnancy complications such as RPL. Given lactate’s established safety in obstetrics and the urgent need for targeted RPL interventions, our work proposes metabolic intervention as a paradigm-shifting, pathology-guided strategy to address RPL pathogenesis. This study therefore bridges evolutionary adaptation with clinical translatability, offering a novel therapeutic framework grounded in placental metabolic resilience.