Ferrostatin-1 protects against necrotizing enterocolitis intestinal injury by inhibiting ferroptosis

Necrotizing enterocolitis (NEC) is a severe neonatal disease marked by intestinal injury, and epithelial damage has been linked to ferroptosis. This study aimed to determine the protective effect of Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, on NEC-associated intestinal injury.

NEC was induced in mouse pups via formula feeding, hypoxia, and lipopolysaccharide exposure. Fer-1 (5 mg/kg) was administered intraperitoneally on postnatal days 6 and 8. Intestinal tissues were analyzed for morphological injury, epithelial proliferation (Ki67), ferroptosis markers (Gpx4 and Tfr1), and lipid peroxidation (4-HNE). Human NEC intestinal organoids derived from surgical samples were treated with Fer-1 (2 µM) for 48 h. Levels of ferrous ion (FerroOrange), lipid peroxide (BODIPY), and reactive oxygen species (DCFDA) were measured.

Fer-1 significantly reduced NEC-induced epithelial injury in mice, leading to improved intestinal morphology and increased epithelial proliferation, as indicated by elevated Ki67 expression. The protective effect was associated with reduced ferroptosis, demonstrated by upregulated Gpx4 expression and decreased levels of Tfr1 and 4-HNE. Similarly, in human NEC organoids, Fer-1 significantly reduced the accumulation of ferrous ions, lipid peroxides, and ROS.

Fer-1 effectively protects against NEC-induced intestinal injury by inhibiting ferroptosis and reducing oxidative stress. These findings highlight its potential as a novel therapeutic strategy for managing intestinal damage in NEC.