Sichuan Key Medical Laboratory of New Drug Discovery and Druggability, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, LuZhou, China.
School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Elife. 2024 Apr 4;13:RP94765. doi: 10.7554/eLife.94765.
Thrombocytopenia caused by long-term radiotherapy and chemotherapy exists in cancer treatment. Previous research demonstrates that 5-Hydroxtrayptamine (5-HT) and its receptors induce the formation of megakaryocytes (MKs) and platelets. However, the relationships between 5-HT1A receptor (5-HTR1A) and MKs is unclear so far. We screened and investigated the mechanism of vilazodone as a 5-HTR1A partial agonist in promoting MK differentiation and evaluated its therapeutic effect in thrombocytopenia. We employed a drug screening model based on machine learning (ML) to screen the megakaryocytopoiesis activity of Vilazodone (VLZ). The effects of VLZ on megakaryocytopoiesis were verified in HEL and Meg-01 cells. Tg (itga2b: eGFP) zebrafish was performed to analyze the alterations in thrombopoiesis. Moreover, we established a thrombocytopenia mice model to investigate how VLZ administration accelerates platelet recovery and function. We carried out network pharmacology, Western blot, and immunofluorescence to demonstrate the potential targets and pathway of VLZ. VLZ has been predicted to have a potential biological action. Meanwhile, VLZ administration promotes MK differentiation and thrombopoiesis in cells and zebrafish models. Progressive experiments showed that VLZ has a potential therapeutic effect on radiation-induced thrombocytopenia in vivo. The network pharmacology and associated mechanism study indicated that SRC and MAPK signaling are both involved in the processes of megakaryopoiesis facilitated by VLZ. Furthermore, the expression of 5-HTR1A during megakaryocyte differentiation is closely related to the activation of SRC and MAPK. Our findings demonstrated that the expression of 5-HTR1A on MK, VLZ could bind to the 5-HTR1A receptor and further regulate the SRC/MAPK signaling pathway to facilitate megakaryocyte differentiation and platelet production, which provides new insights into the alternative therapeutic options for thrombocytopenia.
癌症治疗中存在由长期放疗和化疗引起的血小板减少症。先前的研究表明，5-羟色胺（5-HT）及其受体可诱导巨核细胞（MK）和血小板的形成。然而，5-HT1A 受体（5-HTR1A）与 MK 之间的关系至今尚不清楚。我们筛选并研究了维拉佐酮作为 5-HTR1A 部分激动剂促进 MK 分化的机制，并评估了其在血小板减少症中的治疗效果。我们采用基于机器学习（ML）的药物筛选模型筛选维拉佐酮（VLZ）的巨核细胞生成活性。在 HEL 和 Meg-01 细胞中验证了 VLZ 对巨核细胞生成的影响。通过 Tg（itga2b：eGFP）斑马鱼分析血栓形成的变化。此外，我们建立了血小板减少症小鼠模型，以研究 VLZ 给药如何加速血小板恢复和功能。我们进行了网络药理学、Western blot 和免疫荧光分析，以证明 VLZ 的潜在靶点和通路。VLZ 已被预测具有潜在的生物学作用。同时，VLZ 给药可促进细胞和斑马鱼模型中的 MK 分化和血栓形成。逐步实验表明，VLZ 对体内辐射诱导的血小板减少症具有潜在的治疗作用。网络药理学和相关机制研究表明，Src 和 MAPK 信号通路均参与了 VLZ 促进的巨核细胞生成过程。此外，5-HTR1A 在巨核细胞分化过程中的表达与 Src 和 MAPK 的激活密切相关。我们的研究结果表明，MK 上的 5-HTR1A 表达，VLZ 可以与 5-HTR1A 受体结合，进一步调节 SRC/MAPK 信号通路，促进巨核细胞分化和血小板生成，为血小板减少症的替代治疗选择提供了新的见解。
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