Regulating mitochondrial oxidative phosphorylation and MAPK signaling: wedelolactone as a novel therapeutic for radiation-induced thrombocytopenia

Radiation-induced thrombocytopenia (RIT) is a serious complication of cancer radiotherapy and for which therapeutic options are limited. This study investigates wedelolactone (WED), a metabolite of botanical drug, as a potential treatment for RIT by promoting megakaryocyte differentiation and maturation. In vitro experiments using Meg-01 and K562 cells revealed that WED enhances megakaryocyte differentiation in a dose-dependent manner, increasing the expression of lineagespecific markers CD41 and CD61, and promoting polyploidization and cytoskeletal reorganization. In vivo, WED significantly restored platelet counts in the mice model of RIT, and promoted the production of hematopoietic stem cells (HSCs), megakaryocytes, and reticulated platelets. RNA sequencing and Western blot revealed that WED-induced megakaryocyte differentiation involves the regulation of mitochondrial oxidative phosphorylation mediated by AMPK signaling pathway, and activation of the MAPK signaling pathway. Inhibition of mitochondrial oxidative phosphorylation or MAPK signaling suppressed WED-induced megakaryocyte differentiation, highlighting the central role of these pathways. These findings indicate that WED could be a promising therapeutic candidate for RIT, acting through the modulation of oxidative phosphorylation and MAPK signaling pathway to enhance thrombopoiesis.