Hyperoxia-activated Nrf2 regulates ferroptosis in intestinal epithelial cells and intervenes in inflammatory reaction through COX-2/PGE2/EP2 pathway

Mol Med. 2025 Jan 3;31(1):1. doi: 10.1186/s10020-024-00993-7.

Abstract

The lack of knowledge about the mechanism of hyperoxia-induced intestinal injury has attracted considerable attention, due to the potential for this condition to cause neonatal complications. This study aimed to explore the relationship between hyperoxia-induced oxidative damage and ferroptosis in intestinal tissue and investigate the mechanism by which hyperoxia regulates inflammation through ferroptosis. The study systematically evaluated the effects of hyperoxia on oxidative stress, mitochondrial damage, ferroptosis, and inflammation of intestinal epithelial cells both in vitro and in vivo. The results showed that ferroptosis was involved in intestinal oxidative damage caused by hyperoxia and was regulated by Nrf2. Moreover, hyperoxia-induced oxidative damage regulated inflammation through ferroptosis by upregulating the COX-2/PGE2/EP2 signaling pathway. These findings have important implications for future clinical prevention and therapeutic approaches to neonatal organ injury caused by hyperoxia treatment.

Keywords: COX-2/PGE2/EP2 pathway; Ferroptosis; Hyperoxia; Inflammatory; Intestinal epithelial cells.

MeSH terms

  • Animals
  • Cyclooxygenase 2* / metabolism
  • Dinoprostone* / metabolism
  • Epithelial Cells* / metabolism
  • Ferroptosis*
  • Humans
  • Hyperoxia / metabolism
  • Inflammation* / metabolism
  • Inflammation* / pathology
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Male
  • Mice
  • Mitochondria / metabolism
  • NF-E2-Related Factor 2* / metabolism
  • Oxidative Stress
  • Receptors, Prostaglandin E, EP2 Subtype / genetics
  • Receptors, Prostaglandin E, EP2 Subtype / metabolism
  • Signal Transduction*

Substances

  • NF-E2-Related Factor 2
  • Cyclooxygenase 2
  • Dinoprostone
  • Receptors, Prostaglandin E, EP2 Subtype
  • Nfe2l2 protein, mouse