YC‐4‐3, a Novel Glycogen Synthase Kinase 3β Inhibitor, Alleviates the Endoplasmic Reticulum Stress of Macrophages in Primary Immune Thrombocytopenia

Primary immune thrombocytopenia (ITP) is a heterogeneous autoimmune disease, characterized by decreased platelet count and increased risk of hemorrhage, in which macrophages play an important role in the pathogenesis. This study aims to explore the effects of YC-4-3, the patented chemical synthesis of benzothiazepinone compounds (BTZs), a novel GSK-3β inhibitor (GSK-3βi), on macrophages in ITP. The expressions of GSK-3β in monocytes are tested. The effects of GSK-3βi (YC-4-3) on macrophages of ITP patients are examined and validated in passive and active murine models. Signal pathway enrichment analysis is performed. The interaction proteins of endoplasmic reticulum (ER) stress and GSK-3β are explored. The GSK-3β⁺ cells in monocytes are increased in newly diagnosed ITP patients and decreased in treatment-response patients. YC-4-3 can restrain the proinflammatory differentiation, phagocytosis, and cytokine generation of macrophages and alleviate thrombocytopenia in ITP. YC-4-3 suppresses the PI3K/mTOR/Akt, NFκB/IκBα, and MAPK pathways, as well as the ER stress signal pathway. YC-4-3 directly interacts with the protein chaperone Bip. YC-4-3, a patented GSK-3βi, can modulate the inflammatory status of macrophages and improve the thrombocytopenia in ITP by directly interacting with ER stress response. YC-4-3 may be a novel potential therapeutic agent for ITP.