MELK inhibition promotes megakaryopoiesis and platelet recovery in models of immune thrombocytopenia through ERK/cofilin signaling

Authors:

Xueqian Li, Jiaqian Qi, Tiantian Chu, Qixiu Hou, Haohao Han, Ziyan Zhang, Meng Zhou, Hong Wang, Siyi Lu, Depei Wu, Yue Han

Keywords:

Megakaryocyte; megakaryopoiesis; immune thrombocytopenia; MELK; MAPK/ERK pathway; cofilin

Abstract:

Dysregulated megakaryocyte (MK) maturation is a key feature of immune thrombocytopenia (ITP), yet the specific mechanisms and targeted molecules remain elusive. This study identifies the serine/threonine kinase maternal embryonic leucine zipper kinase (MELK) as a potential regulator of megakaryopoiesis in ITP. MELK expression is significantly elevated in bone marrow MKs of patients with ITP compared with healthy donors and inversely correlates with platelet counts. Functionally, inhibition of MELK not only promotes MK maturation in vitro but also promotes platelet recovery in the ITP mouse model. Mechanistic studies reveal that MELK modulates megakaryopoiesis through the MAPK/ERK pathway. Confocal microscopy and western blot verifications indicate that MELK inhibition reduces cofilin phosphorylation, thereby positively regulating cytoskeletal dynamics, and this effect is abrogated by MAPK/ERK blocking. These findings suggest that MELK inhibition promotes MK maturation and platelet production via the MAPK/ERK/cofilin axis, providing a potential for the development of therapeutic options for ITP.

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