Ferulic acid promotes thrombopoiesis via TLR4/JAK2/STAT3 signaling: A novel therapeutic strategy for thrombocytopenia

Thrombocytopenia, a common hematological disorder, is associated with increased mortality in various diseases. However, the existing clinical treatments are often accompanied by various adverse effects and may even disrupt platelet homeostasis, highlighting the urgent need to develop novel therapeutic agents. Here, we developed a drug screening model based on virtual screening utilizing known monomeric components of Sanguisorba officinalis L. (SOL) and identified ferulic acid (FA) as a promising candidate for thrombocytopenia intervention. In vitro study using Meg-01 and K562 cell lines demonstrated that FA enhanced the megakaryocyte (MK) maturation. In vivo, thrombopoietic effects were evaluated in Tg (itga2b:eGFP) transgenic zebrafish, revealing significant modulation of platelet production. Furthermore, in a thrombocytopenia mouse model, FA treatment increased megakaryocyte progenitors (MKPs) and MKs numbers in the bone marrow and spleen, inhibited oxidative stress and apoptosis in the bone marrow, and stimulated new platelet production in peripheral blood, thereby accelerating platelet count and function. Importantly, FA did not disrupt the platelet homeostasis in normal mice. Mechanistically, FA was identified as a direct activator of Toll-like receptor 4 (TLR4), which in turn activated the JAK2/STAT3 signaling pathway, thereby promoting MK differentiation and thrombopoiesis. These findings present FA as a potential novel therapeutic strategy for thrombocytopenia and provide a basis for its clinical development as an alternative or adjunctive therapy.