Ferroptosis in necrotizing enterocolitis: iron overload-driven intestinal injury and mechanistic insights

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal emergency that primarily affects preterm infants and remains associated with high mortality and significant long-term morbidity. Despite decades of research, the precise mechanisms underlying NEC pathogenesis remain incompletely understood, and effective targeted preventive or therapeutic strategies are limited. Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has recently emerged as an important contributor to intestinal epithelial injury in NEC. Preterm infants are particularly vulnerable to ferroptosis due to immature iron homeostasis, frequent exposure to exogenous iron through supplementation and blood transfusion, heightened oxidative stress, and insufficient antioxidant capacity. Accumulating experimental evidence indicates that iron overload promotes excessive lipid peroxidation, glutathione depletion, and inactivation of key antioxidant enzymes, leading to ferroptotic death of intestinal epithelial cells. This process compromises intestinal barrier integrity, amplifies inflammatory signaling, and interacts with gut microbiota dysbiosis, thereby accelerating NEC progression. In this review, we summarize current advances in understanding the role of ferroptosis in NEC, with an emphasis on iron overload as a central upstream driver and ferroptosis as a convergent execution pathway linking multiple pathogenic factors. We discuss evidence from experimental and translational studies, explore the crosstalk between ferroptosis, inflammation, and the gut microbiota, and outline potential therapeutic implications of targeting ferroptosis. A ferroptosis-centered framework may provide novel insights into NEC pathogenesis and guide future mechanistic and translational research.