Related Experiment Video
Updated: May 21, 2026
In Vitro Apical-Out Enteroid Model of Necrotizing Enterocolitis
Published on: June 8, 2022
Elucidating shared genes and pathways in programmed cell death with necrotizing enterocolitis: insights into novel
Pengjian Zou1,2, Qiuming He2, Longlong Hou2
1Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
Background:
Necrotizing enterocolitis (NEC) is a severe neonatal intestinal disease with high mortality, and effective pharmacological therapies remain limited. Increasing evidence suggests that multiple forms of programmed cell death are involved in NEC pathogenesis. Glutathione (GSH), has shown potential protective effects against oxidative stress and inflammation injury, but its role and underlying mechanisms in NEC remain unclear. This study aimed to elucidate the shared molecular mechanisms underlying ferroptosis, pyroptosis, necroptosis and autophagy in NEC, and to investigate the protective role and regulatory pathways of GSH against these forms of programmed cell death.
Methods:
To address these knowledge gaps, we comprehensively analyzed ferroptosis, pyroptosis, necroptosis, and autophagy gene sets from GeneCards and microarray data for NEC, aiming to identify shared differentially expressed genes (DEGs) biomarkers and pathways involved in programmed cell death during NEC pathogenesis. A series of bioinformatics analyses were performed, including Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses, protein-protein interaction (PPI) networks, biological characterization, and transcription factors (TFs)-gene interactions. Key regulators of cell death were further validated in NEC mouse model, Caco-2 experiments, and clinical samples. Additionally, the potential interactions between GSH and hub genes encoded proteins were preliminarily explored by molecular docking.
Results:
In this study, 11 potential target genes associated with both NEC and cell death were identified by intersecting DEGs. Subsequently, six hub genes (TLR4, NLRP3, NFKB1, NFKBIA, VIM, ANXA1) were screened from the PPI network using Cytoscape. Correlation and immune infiltration analyses indicated that these hub genes were closely linked to inflammation in NEC. The expression of the hub genes was significantly elevated in NEC, as confirmed by both NEC mouse models and Caco-2 cell-based models. Treatment of NEC mice with GSH significantly reduced the expression of TLR4, NLRP3 and NFKB1. Molecular docking analysis indicated binding interactions of GSH to TLR4 and NFKB1 proteins. Elevated expression of TLR4, NLRP3 and NFKB1 was also validated in intestinal tissue samples from NEC patients.
Conclusions:
TLR4, NLRP3 and NFKB1 represent shared molecular mediators of ferroptosis, pyroptosis, necroptosis and autophagy in the pathogenesis of NEC. GSH may alleviate intestinal necrosis in NEC by downregulating the expression of TLR4, NLRP3 and NFKB1.
Related Concept Videos
01:16Necrosis
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become anucleated and die, but their...
01:22Cellular Injury V: Apoptosis and Autophagy
01:17The Extrinsic Apoptotic Pathway
01:30Overview of Cell Death
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the 20th century...