Ferroptosis-targeted pharmacotherapeutic strategies in pregnancy complications: A systematic review of translational maternal–fetal therapeutics

Ferroptosis has emerged as a biologically distinct form of regulated cell death characterized by iron-dependent lipid peroxidation, yet its relevance in pregnancy has only recently started to receive focused attention. Pregnancy represents a unique physiological state in which maternal adaptation, placental development, immune regulation, and fetal growth are tightly interconnected. Small disruptions in these systems can evolve into clinically significant disorders. Interestingly, a recurring pattern across several pregnancy complications, including preeclampsia, recurrent miscarriage, fetal growth restriction, and placental dysfunction, is the presence of oxidative stress, altered iron handling, and trophoblast injury. These observations raise an important question: are these isolated findings or do they represent different expressions of a shared ferroptotic process? This systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses principles to evaluate current evidence regarding ferroptosis-related mechanisms and potential pharmacotherapeutic strategies in pregnancy complications within a translational maternal–fetal framework. Thirty-one studies were included following structured screening and eligibility assessment. The evidence consistently suggested that disturbances involving glutathione peroxidase 4, solute carrier family 7 member 11, nuclear factor erythroid 2–related factor 2 (Nrf2), hypoxia-inducible factor-related signaling, lipid reactive oxygen species generation, and iron metabolism contribute to placental ferroptotic susceptibility. Several experimental interventions, including selenium supplementation, Nrf2 activation, NADPH oxidase 2 inhibition, puerarin, L-arginine, and iron-modulating strategies, demonstrated protective effects against ferroptosis-associated injury. At the same time, the literature reveals an uneven landscape. Mechanistic insights are expanding rapidly, whereas clinically validated therapeutic approaches remain limited. Ferroptosis appears to represent more than an isolated molecular event; it may function as a biologically convergent pathway linking placental dysfunction with adverse maternal and fetal outcomes. Further translational studies and prospective clinical investigations are required before ferroptosis-guided therapeutic approaches can be incorporated into maternal–fetal medicine.