Ginkgolic acid: a novel IL1R1 agonist facilitating megakaryocyte differentiation and platelet production via the SRC/MEK/ERK pathway.

Abstract

Thrombocytopenia, a common complication of prolonged radiotherapy in cancer patients, presents significant clinical management challenges due to limitations of current therapies. In this study, we screened Ginkgolic acid (GA) and elucidated its mechanisms in regulating the differentiation of Megakaryocytes (MKs) and thrombopoiesis, as well as its therapeutic potential for thrombocytopenia. Firstly, Initial validation studies conducted in vitro using K562, Meg-01 cell lines and mouse primary MK showed that GA promoted MK differentiation, which evidenced by increased cell size, enhanced polyploidization, and upregulation of specific markers. Subsequently, validation of GA's effect on platelet production was undertaken using the radiation-induced thrombocytopenia (RIT) model mice and the RIT Tg (itga2b: eGFP) model zebrafish. GA stimulated thrombopoiesis in RIT Tg (itga2b: eGFP) zebrafish and accelerated thrombopoiesis and restored platelet function in RIT model mice. Furthermore, integrated approaches combining network pharmacology, western blotting, and immunofluorescence revealed that GA exerts these effects through IL1R1 receptor activation and subsequent modulation of the SRC/MEK/ERK signaling pathway. In summary, the present study provides novel insights into the pharmacological effects of GA. GA as a novel IL1R1 agonist, promotes MK differentiation and platelet formation via downstream pathway of SRC/MEK/ERK, suggesting that GA's potential as a therapeutic candidate for treating RIT.