Targeting CCR5 with miltefosine as a therapeutic strategy for thrombocytopenia
Qinyao Li, Ting Zhang, Zhichao Li, Xiao Qi, Xinyue Mei, Sheng Liu, Siyu He, Gan Qiao, Rong Li, Hongping Shen, Jing Zeng, Feihong Huang, Shuang Dai, Sirui Li, Jiesi Luo, Jianming Wu, Long Wang
TL;DR
Miltefosine promotes platelet production by targeting CCR5 and activating key signaling pathways, offering a new treatment for thrombocytopenia.
Contribution
Miltefosine is identified as a CCR5 agonist that promotes megakaryocyte differentiation and platelet recovery via MAPK and JAK2/STAT3 pathways.
Findings
Miltefosine accelerates platelet recovery and enhances function in irradiated mice.
Miltefosine directly binds to CCR5 and activates MAPK and JAK2/STAT3 signaling pathways.
Inhibition of CCR5 or these pathways disrupts miltefosine's effects on megakaryocyte differentiation.
Abstract
Thrombocytopenia remains a challenging clinical condition with limited treatment options. Here, we demonstrated that miltefosine stimulated megakaryocyte (MK) differentiation in vitro. Miltefosine significantly accelerated platelet recovery, enhanced platelet function, and boosted MK production and differentiation in irradiated mice. RNA sequencing revealed association of CCR5, MAPK, and JAK2/STAT3 signaling pathways in miltefosine-mediated MK differentiation. Molecular docking, drug affinity responsive target stability (DARTS), and surface plasmon resonance (SPR) assays confirmed direct binding of miltefosine to CCR5. Inhibition of CCR5 disrupted miltefosine’s effects on MK differentiation and activation of MAPK and JAK2/STAT3 signaling pathways, as well as key transcription factors GATA1, EGR1, and TAL1. Similarly, blockade of the MAPK or JAK2/STAT3 signaling pathways hindered…
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Taxonomy
TopicsGalectins and Cancer Biology · Phytochemical compounds biological activities · Reproductive System and Pregnancy