Ferroptosis–pyroptosis crosstalk in neonatal necrotizing enterocolitis: epithelial barrier failure, immune amplification, and precision targeting
Year: 2026
Type: review
Abstract: Necrotizing enterocolitis (NEC) is a rapidly progressive intestinal emergency of preterm infants in which epithelial injury, dysregulated innate immunity, microvascular failure and microbial translocation reinforce one another. Ferroptosis and pyroptosis have emerged as complementary components of this process. Ferroptosis is driven by iron-dependent phospholipid peroxidation and failure of the SLC7A11-glutathione-GPX4 defense system, whereas pyroptosis is executed by inflammasome-activated gasdermins with release of interleukin-1β, interleukin-18 and damage-associated molecular patterns. Recent NEC studies implicate epithelial ferroptosis, inflammasome-GSDMD activation, mitochondrial dysfunction, and immune-cell death programs across epithelial, myeloid, lymphoid, and platelet compartments. Current data support convergence through redox stress, mitochondrial injury, damage-associated molecular patterns (DAMPs), and barrier failure; however, coexistence of ferroptotic and pyroptotic signals should not be interpreted as proven reciprocal crosstalk. Direct causal coupling between these pathways in human NEC remains unconfirmed. This Mini Review integrates epithelial, immune and vascular evidence; evaluates candidate biomarkers including HMGB1, intestinal fatty acid-binding protein, S100A12, DEFA6 and lipopolysaccharide-binding protein; and proposes a precision-targeting framework. Human milk-based supportive strategies are clinically relevant, whereas FXR/ACSL4 modulation, ferroptosis inhibitors, NLRP3/GSDMD blockade, and mitophagy-directed interventions remain predominantly experimental in NEC. Progress will require cell-resolved human validation, longitudinal biomarker panels and developmentally appropriate combination strategies that interrupt the death-inflammation cycle without impairing host defense or intestinal maturation.
Authors: Juan He, Yu Gu, Shanshan An, Liwei Yan, Xuhua Song
Institution: Affiliated Hospital of Hebei University
Language: English
Topic: Infant Nutrition and Health
Subfield: Nutrition and Dietetics
Field: Nursing
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7221758513