Necrotizing enterocolitis (NEC) is a leading gastrointestinal emergency in preterm infants, characterized by severe epithelial injury, dysregulated inflammation, and defective mucosal repair. Intestinal stem cells (ISCs) at the crypt base are essential for epithelial renewal and barrier restoration after injury.

We summarized recent advances in the molecular and cellular mechanisms governing ISC injury and regeneration in NEC, emphasizing canonical repair pathways, niche-derived regulatory circuits, and emerging ISC-targeted therapies.

NEC disrupts ISC survival, proliferation, and differentiation through aberrant innate immune activation, microbial dysbiosis, and impairment of Wnt, Notch, and epidermal growth factor (EGF) signalling. ISC function is also shaped by interactions with Paneth cells, mesenchymal niche components, immune cells, and microbial metabolites. Disruption of this niche compromises crypt regeneration, perpetuates barrier dysfunction, and amplifies intestinal inflammation. Restoring ISC activity and niche integrity has therefore prompted interest in growth factor supplementation, microbiota modulation, immune-based interventions, and stem cell-oriented approaches.

ISC-centred regenerative failure provides an integrated framework linking epithelial biology, immunology, and microbiome research in NEC. Restoring ISC function and niche integrity represents a promising therapeutic direction with experimental and translational relevance.