用米替福新靶向 CCR5 作为血小板减少症的治疗策略

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-04-08 DOI:10.1016/j.isci.2025.112379

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

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引用次数: 0

摘要

血小板减少症仍然是一种具有挑战性的临床病症，治疗方案有限。在此，我们证实米替福新能刺激体外巨核细胞（MK）分化。米替福新能明显加快血小板的恢复，增强血小板功能，促进辐照小鼠的巨核细胞生成和分化。RNA 测序显示，CCR5、MAPK 和 JAK2/STAT3 信号通路与米替福新介导的 MK 分化有关。分子对接、药物亲和力反应目标稳定性（DARTS）和表面等离子体共振（SPR）测定证实了米替福新与CCR5的直接结合。抑制 CCR5 会破坏米替福新对 MK 分化、MAPK 和 JAK2/STAT3 信号通路的激活以及关键转录因子 GATA1、EGR1 和 TAL1 的影响。同样，阻断MAPK或JAK2/STAT3信号通路也会阻碍米替福新诱导的MK分化和转录因子激活。我们的研究结果确定了 CCR5 是血小板减少症的治疗靶点，并确定了米替福新是一种 CCR5 激动剂，可通过 MAPK 和 JAK2/STAT3 信号传导促进 MK 分化和血小板生成。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Targeting CCR5 with miltefosine as a therapeutic strategy for thrombocytopenia

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Targeting CCR5 with miltefosine as a therapeutic strategy for thrombocytopenia

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 miltefosine-induced MK differentiation and transcription factor activation. Our findings establish CCR5 as a therapeutic target for thrombocytopenia and identify miltefosine as a CCR5 agonist that promotes MK differentiation and platelet production via MAPK and JAK2/STAT3 signaling.

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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