Metabolic imprinting in trophoblast barrier dysfunction: the role of glucolipotoxicity, endoplasmic reticulum stress, and amino acid transport imbalance.

The syncytiotrophoblast is central to maternal-fetal exchange and endocrine regulation, with its barrier integrity ensuring nutrient supply, immune defense, and metabolic balance. Maternal metabolic disturbances induce metabolic imprinting, whereby epigenetically regulated imprinted genes alter trophoblast physiology, nutrient transport, and growth signaling. Aberrant imprinting amplifies oxidative, inflammatory, and endoplasmic reticulum stress, impairing trophoblast differentiation, fusion, and hormone synthesis. A salient outcome is disruption of amino acid transport and the mechanistic target of rapamycin (mTOR) signaling, restricting fetal nutrient delivery and promoting growth restriction. This review synthesizes current evidence linking metabolic imprinting, stress responses, and transporter dysfunction as a multifactorial basis for syncytiotrophoblast failure and pregnancy complications. Further discussions on emerging stress-related biomarkers and potential therapeutic strategies, including antioxidants, metabolic modulators, and nutritional interventions, to restore placental efficiency. Metabolic imprinting establishes a pathological memory within the placenta, rendering it vulnerable to maternal metabolic insults and predisposing offspring to long-term metabolic disorders. Targeting these interconnected pathways may offer early opportunities for intervention and improved pregnancy outcomes.