The Emerging Roles of Ferroptosis and NETosis in Pregnancy Complications: Insights into Preeclampsia and Gestational Diabetes Mellitus
Vasiliki Katsi, Angeliki Alifragki, Konstantinos Fragkiadakis, Nikolaos Kopidakis, E. M. Kallergis, Evangelos Zacharis, Emmanouil Kampanieris, Emmanouil Simantirakis, Konstantinos Tsioufis, Maria Marketou
Abstract
Gestational complications, such as preeclampsia and gestational diabetes mellitus (GDM), pose significant risks to maternal and fetal health and increase long-term cardiovascular disease risk in offspring. This review aims to synthesize current knowledge on the roles of ferroptosis and neutrophil extracellular trap formation (NETosis)-two regulated cell death pathways-in these pregnancy-related conditions. We performed a comprehensive analysis of preclinical and clinical studies that investigate the involvement of dysregulated iron metabolism, oxidative stress, inflammation, and endothelial dysfunction mediated by ferroptosis and NETosis in gestational pathologies. Evidence indicates that disturbances in maternal iron homeostasis and enhanced formation of lipid peroxides and NETs contribute to placental dysfunction and systemic inflammation, exacerbating disease severity. Therapeutic strategies targeting these pathways are emerging but require further validation. Our review also identifies key gaps in mechanistic understanding, biomarker development, and translational research needs. We conclude that modulation of ferroptosis and NETosis offers promising avenues for improving diagnosis and treatment of pregnancy complications, though carefully designed clinical studies are essential to confirm their clinical utility and safety.