Integrative analysis links ferroptosis to necrotizing enterocolitis and reveals the role of ACSL4 in immune disorders

Multiple types of regulated cell death (RCD) have been demonstrated to cause gut barrier dysfunction in necrotizing enterocolitis (NEC); however, whether and how ferroptosis is involved in NEC remains unknown. Here, ferroptosis was identified to play a role in NEC using bioinformatics analyses and wet experiments. Inhibition of ferroptosis significantly alleviated NEC in newborn mice. ACSL4 expression levels were augmented and positively correlated with ferroptosis in NEC. Surprisingly, ACSL4 was critically correlated with multiple types of RCD, including autophagy, apoptosis and pyroptosis, as well as hypoxia and inflammation. Besides, ACSL4 was positively correlated with the abundance of multiple types of immune cells, including macrophage, activated dendritic cell, neutrophil and regulatory T cell. Conclusively, we first identified the involvement and role of ferroptosis in NEC and revealed the potential effects of ACSL4 on immune disorders, which could provide a rationale for future research on ferroptosis in NEC.