The IL-33/ST2 Signaling Axis Alleviates Splenic Injury in Severe Acute Pancreatitis by Inhibiting T Cell Ferroptosis.

Pancreas 2026

Cui L, Xu N, Chen J, Bin C, Feng Y et al.

Abstract

OBJECTIVES: This study aimed to investigate whether the IL-33/ST2 signaling axis alleviates SAP-induced splenic injury by regulating ferroptosis in T lymphocytes. METHODS: A murine SAP model was established via intraperitoneal injection of cerulein and lipopolysaccharide (LPS). Recombinant IL-33 was administered intraperitoneally. Histopathological changes, inflammatory cytokines, ferroptosis-related indicators (MDA, Fe2+, GSH, GPX4, ACSL4, FTH1), mitochondrial function (mtDNA, ATP, mitochondrial ROS (mito-SOX), membrane potential), and ultrastructural alterations were assessed. In vitro, Concanavalin A-stimulated splenic T cells were treated with IL-33, the ferroptosis inhibitor Ferrostatin-1 (Fer-1), or the ST2 antagonist soluble ST2 (sST2) to validate the pathway. RESULTS: IL-33 treatment significantly alleviated pancreatic and splenic histopathological damage, reduced systemic inflammation, and inhibited ferroptosis in the spleen, as evidenced by attenuated lipid peroxidation, attenuated glutathione depletion, and normalized expression of key ferroptosis regulators (GPX4, ACSL4, FTH1). Concurrently, IL-33 improved mitochondrial function and attenuated oxidative stress. In vitro, IL-33 directly inhibited ConA-induced T cell ferroptosis, an effect mimicked by Fer-1. Crucially, all protective effects of IL-33 were abolished by sST2, confirming that its action is specifically dependent on the ST2 receptor. CONCLUSIONS: The IL-33/ST2 axis exerts a protective effect in SAP by inhibiting T cell ferroptosis, improving mitochondrial function, and maintaining redox homeostasis, highlighting its potential as a therapeutic target.

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