The Molecular Landscape of Placental Dysfunction in Fetal Growth Restriction (FGR): From Integrated Signaling Networks to Epigenetic Control

Fetal growth restriction (FGR) is a major pregnancy complication linked to placental insufficiency, resulting from defective trophoblast differentiation, impaired maternal-fetal vascular adaptation, and altered nutrient sensing. This review synthesizes current evidence on the interconnected molecular networks driving placental dysfunction. We map the reciprocal crosstalk between the pro-inflammatory shift, highlighted by NLRP3 inflammasome-driven trophoblast pyroptosis, and dysregulated extracellular matrix remodeling mediated by the MMP-9/TIMP system. This hostile microenvironment feeds directly into the angiogenic imbalance defined by the sFlt-1/PlGF ratio, accelerating cellular senescence via p53 and disrupting survival hubs like the PTEN/PI3K/AKT axis. Consequently, downstream metabolic sensors, notably the mTOR pathway, are blunted, causing trafficking failure of essential amino acid (SNAT2, LAT1) and glucose (GLUT) transporters. Crucially, we introduce an original framework integrating emerging spatial transcriptomics and single-cell epigenomics, demonstrating that these pathomechanisms are anatomically regionalized rather than uniform. Finally, we provide a critical evaluation of translation-ready therapeutic targets, emphasizing that strict safety constraints against fetal teratogenesis render ligand-functionalized nanoparticles a non-negotiable prerequisite for placenta-selective drug delivery. Integrating molecular stratification with longitudinal biomarker profiling represents the next milestone for mechanism-based, targeted management of FGR.