Ferroptosis-pyroptosis crosstalk in neonatal necrotizing enterocolitis: epithelial barrier failure, immune amplification, and precision targeting.
4 affiliations
- 1Department of Pediatrics, Affiliated Hospital of Hebei University, Baoding, Hebei, China.
- 2Department of Pharmacy, Affiliated Hospital of Hebei University, Baoding, Hebei, China.
- 3Department of Gynecology, Affiliated Hospital of Hebei University, Baoding, Hebei, China.
- 4Department of Otorhinolaryngology, Affiliated Hospital of Hebei University, Baoding, Hebei, China.
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.
Related
- Sphingosine-1-phosphate ameliorates necrotizing enterocolitis by regulating mitochondrial redox homeostasis and gut microbiota.
- Energy Metabolic Reprogramming Characterized by Succinate Accumulation Aggravates Necrotizing Enterocolitis.
- Nur77 Restrains Caspase-11-associated Macrophage Pyroptosis and Inflammatory Amplification During Early Sepsis
- Inflammatory cell death in cancer: linking pyroptosis, necroptosis, ferroptosis, PANoptosis, and antitumor immunity
- Mitochondrial quality control at the ferroptosis-pyroptosis interface in diabetic cardiomyopathy: a narrative critical synthesis
BibTeX
@article{he2026ferroptosispyroptosis,
title = {{Ferroptosis-pyroptosis crosstalk in neonatal necrotizing enterocolitis: epithelial barrier failure, immune amplification, and precision targeting.}},
author = {Juan He and Yu Gu and Shanshan An and Liwei Yan and Xuhua Song},
journal = {Frontiers in cell and developmental biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1981457},
url = {https://europepmc.org/article/MED/42953087},
note = {CC BY},
}
RIS
TY - JOUR
TI - Ferroptosis-pyroptosis crosstalk in neonatal necrotizing enterocolitis: epithelial barrier failure, immune amplification, and precision targeting.
AU - Juan He
AU - Yu Gu
AU - Shanshan An
AU - Liwei Yan
AU - Xuhua Song
PY - 2026
DA - 2026/10/14
JO - Frontiers in cell and developmental biology
DO - 10.3389/fcell.2026.1981457
UR - https://europepmc.org/article/MED/42953087
AB - 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.
SN - 2296-634X
ER -