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

作者：Lijian Cui, Ning Xu, Jianhong Chen, Chuxuan Bin, Yue Feng, Baona Guo, Enjie Zhang, Yingyi Luan, C. Cameron Yin · 发表于：Pancreas · 年份：2026 · DOI：10.1097/mpa.0000000000002654 · 研究领域：IL-33, ST2, and ILC Pathways、Ferroptosis and cancer prognosis、Pancreatitis Pathology and Treatment

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 through intraperitoneal injection of cerulein and lipopolysaccharide (LPS). Recombinant IL-33 was administered intraperitoneally. Histopathologic changes, inflammatory cytokines, ferroptosis-related indicators (MDA, Fe 2+ , GSH, GPX4, ACSL4, FTH1), mitochondrial function [mtDNA, ATP, mitochondrial ROS (mito-SOX), and 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 histopathologic 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 SA...