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. 2025 Jul 1;111(7):4314-4324.
doi: 10.1097/JS9.0000000000002541. Epub 2025 May 20.

Ferroptosis is involved in the IL-9-induced intestinal barrier injury in sepsis: an experimental animal and translational study

Jia-Kui Sun  1 , Xiao-Tian Huangfu  1 , Xiang Yin  1 , Shuai Nie  1 , Yi-Hang Deng  1 , Zi-Yu Ye  1 , Xue-Hui Zhou  1 , Xiang Wang  1 , Yan-Na Si  2
Affiliations

Ferroptosis is involved in the IL-9-induced intestinal barrier injury in sepsis: an experimental animal and translational study

Jia-Kui Sun et al. Int J Surg. .

Abstract

Background: Interleukin-9 (IL-9) is an emerging pro-inflammatory cytokine that promotes intestinal barrier injury (IBI) in sepsis. The specific mechanisms of IL-9-induced IBI still need to be clarified. As a newly discovered form of programmed cell death, ferroptosis was demonstrated to be involved in sepsis-related organ dysfunction, yet its role in IL-9-induced IBI in sepsis remains unexplored.

Methods: Serum levels of IL-9, D-lactate, intestinal fatty acid binding protein (iFABP), glutathione (GSH), and glutathione peroxidase 4 (GPX4) were tested in septic patients and control subjects. Biomarkers reflecting barrier function in serum and intestinal tissue were tested in treated rats. Rats underwent sepsis induction, IL-9, IL-9 inhibition (IL-9i), and ferroptosis inhibition (Fei) treatment were selected to examine the severity of IBI and survival rates.

Results: Significantly elevated levels of IL-9, D-lactate, iFABP, GSH, and GPX4 were observed in septic patients and rats. IL-9 levels showed a negative correlation with GSH and GPX4 levels, while GSH or GPX4 levels showed an inverse correlation with D-lactate and iFABP levels. Serum GSH and GPX4 levels demonstrated strong predictive value for acute gastrointestinal injury of grade II and above in septic patients. IL-9 administration increased levels of transferrin receptor, Fe 2+ , and iFABP in serum and intestinal tissue of septic rats, while decreasing GSH, GPX4, and zonula occludens 1 levels. Inhibition of ferroptosis reversed these biomarkers alterations. Intestinal permeability, transmission electron microscopy, histopathology, and apoptosis assays confirmed exacerbated IBI following IL-9 upregulation and its attenuation upon ferroptosis inhibition.

Conclusion: Ferroptosis was implicated in the IL-9-induced intestinal barrier injury in sepsis.

Keywords: IL-9; ferroptosis; intestinal mucosal barrier; sepsis.

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