Epigenetic silencing of ferroptosis-regulating genes (PCBP1, GPX4, FTL) in cord blood: identification of novel biomarkers of fetal growth restriction induced by maternal smoking

Maternal smoking is a leading preventable cause of intrauterine growth restriction (IUGR). While the clinical association is well-established, the molecular mechanisms linking prenatal smoke exposure and reduced fetal growth remain unclear. Ferroptosis, an iron-dependent form of cell death, has been implicated in placental pathology. This study aimed to validate epigenetic alterations in the ferroptosis pathway as potential biomarkers of smoking-induced fetal damage. We analyzed umbilical cord blood from 40 newborns stratified into four groups based on maternal smoking status and birth weight. Methylation levels of ferroptosis-regulating genes (PCBP1, GPX4, FTL) were quantified using MeDIP-qPCR. Maternal smoking induced significant hypermethylation of the iron chaperone PCBP1 (Fold Change = 2.04; p = 1.32×10 − 9) and the antioxidant enzyme GPX4 (p = 2.46×10 − 5). The silencing effect was most pronounced in the "Smoker-Low Birth Weight" group. Additionally, FTL showed hypermethylation associated with low birth weight even in non-smokers (FC = 1.48; p = 0.005), suggesting an adaptive response to growth restriction. Prenatal tobacco exposure triggers targeted epigenetic silencing of the fetal antioxidant and iron-transport machinery. We identify PCBP1 hypermethylation as a highly sensitive biomarker of smoking-induced fetal stress. These findings suggest that ferroptosis is a key mechanism in the pathogenesis of IUGR and highlight potential targets for early detection and preventive strategies.