Death by Iron: Ferroptosis in the Aetiology and Outcome of Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is a common metabolic complication during pregnancy that poses significant risks to both maternal and foetal health. Although its pathogenesis is multifactorial, emerging evidence highlights a potential role of iron metabolism and its dysregulation in the development of GDM. Iron is essential for foetal growth and maternal physiological adaptation during pregnancy. However, both iron deficiency and excess iron are associated with adverse pregnancy outcomes. In particular, excess iron accumulation has been associated with elevated oxidative damage and impaired glucose regulation, potentially contributing to the onset of GDM. Ferroptosis, a regulated cell death caused by iron-dependent lipid peroxidation, has recently emerged as a potential mechanistic link between iron overload and cellular dysfunction in GDM. This review highlights the dynamic regulation of iron metabolism during normal pregnancy and its disruption in GDM. In the context of GDM, ferroptosis is implicated in promoting oxidative stress and lipid peroxidation that disrupts metabolic regulation. Existing research suggests that maternal iron status could serve as a biomarker for early GDM risk assessment and a potential therapeutic target. However, the molecular pathways linking iron metabolism, ferroptosis, and metabolic abnormalities remain uncertain. Further investigations are needed to understand these mechanisms and assess the potential of ferroptosis inhibitors in GDM. Bridging these knowledge gaps could lead to improved strategies for the prediction, prevention, and management of GDM and its associated complications.