Ischemia-reperfusion injury (IRI) results in irreversible metabolic dysfunction and structural damage to tissues or organs, posing a formidable challenge in the field of organ implantation, cardiothoracic surgery, and general surgery. Glycogen synthase kinase-3β (GSK-3β) a multifunctional serine/threonine kinase, is involved in a variety of biological processes, including cell proliferation, apoptosis, and immune response. Phosphorylation of its tyrosine 216 and serine 9 sites positively and negatively regulates the activation and inactivation of the enzyme. Significantly, inhibition or inactivation of GSK-3β provides protection against IRI, making it a viable target for drug development. Though numerous GSK-3β inhibitors have been identified to date, the development of therapeutic treatments remains a considerable distance away. In light of this, this review summarizes the complicated network of GSK-3β roles in IRI. First, we provide an overview of GSK-3β's basic background. Subsequently, we briefly review the pathological mechanisms of GSK-3β in accelerating IRI, and highlight the latest progress of GSK-3β in multiorgan IRI, encompassing heart, brain, kidney, liver, and intestine. Finally, we discuss the current development of GSK-3β inhibitors in various organ IRI, offering a thorough and insightful reference for GSK-3β as a potential target for future IRI therapy.
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