IFI27-mediated regulation of regulatory T cells aggravates lung injury in sepsis via IL-10/STAT3 signaling.

Background and purpose: Interferon-induced protein 27 (IFI27) is implicated in immune regulation, and regulatory T cells (Tregs) play a critical role in maintaining pulmonary immune homeostasis during sepsis. However, the relationship between IFI27 and Treg-mediated regulation in sepsis-associated lung injury remains unclear. This study aimed to investigate the role of IFI27 in modulating Treg function during sepsis. Methods: Plasma IFI27 levels were measured in patients with sepsis and healthy controls. mRNA sequencing was performed to assess IFI27 expression profiles. Results: Clinical analyses demonstrated that plasma IFI27 levels were positively correlated with sepsis severity. IFI27 expression was significantly increased in septic mice. Elevated IFI27 inhibited STAT5 phosphorylation, leading to a reduction in Treg abundance and IL-10 secretion, thereby exacerbating ferroptosis in pulmonary epithelial cells. Furthermore, IFI27 elevation in Tregs increased lipid peroxidation levels by suppressing the IL-10/STAT3 signaling pathway. Conclusions: These findings indicate that IFI27 is closely associated with sepsis severity and may serve as a potential prognostic indicator. Mechanistically, IFI27 suppresses Treg function and enhances ferroptosis in lung epithelial cells through inhibition of the IL-10/STAT3 signaling pathway, thereby aggravating sepsis-induced lung injury.