Therapeutic Targeting of IL-33 in Ischemia-Reperfusion Injury: Progress and Prospects

Ischemia-Reperfusion Injury (IRI) is a prototypical sterile inflammatory process that complicates solid-organ transplantation, reperfusion therapy for acute myocardial infarction, and revascularization procedures. Clinical management relies largely on supportive and procedural measures; no specific targeted therapy is available. Interleukin-33 (IL-33), a multifunctional member of the IL-1 cytokine family, is constitutively localized to the nucleus in several structural cell types and acts extracellularly as an alarmin after release. The IL-33/ST2 signaling axis has been implicated in multiple phases of IRI. This review describes the conserved core of the IL-33/ST2 signaling cascade. It also examines the regulatory mechanisms and functional heterogeneity of IL-33 across six major IRI-susceptible organ systems: the cardiovascular system, kidney, liver, lung, brain, and gastrointestinal tract. Available evidence suggests a recurrent but not universal pattern: IL-33 can amplify acute sterile inflammation in some organs and models, yet support inflammation resolution and tissue repair in other settings or at later stages. The effects of IL-33 depend on the organ involved, the cellular source of IL-33, the spatial distribution of ST2-expressing target cells, the local microenvironment, and the phase of injury and timing of intervention. This review summarizes recent preclinical advances in IL-33/ST2-targeted strategies and discusses the principal challenges to their clinical translation. These include limited human efficacy and safety data, the lack of clinically feasible intervention strategies, and the absence of validated companion biomarkers. The IL-33/ST2 axis may be an organ- and context-specific therapeutic target for IRI, but further validation is required before clinical application.