Oxymatrine,a novel TLR2 agonist,promotes megakaryopoiesis and thrombopoiesis through the STING/NF-κB pathway
10.1016/j.jpha.2024.101054
- Author:
Chengyang NI
1
;
Ling ZHOU
;
Shuo YANG
;
Mei RAN
;
Jiesi LUO
;
Kui CHENG
;
Feihong HUANG
;
Xiaoqin TANG
;
Xiang XIE
;
Dalian QIN
;
Qibing MEI
;
Long WANG
;
Juan XIAO
;
Jianming WU
Author Information
1. 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,Sichuan,646000,China
- Publication Type:Journal Article
- Keywords:
Oxymatrine;
Megakaryocyte differentiation;
Thrombopoiesis;
Platelets;
Toll-like receptor 2
- From:
Journal of Pharmaceutical Analysis
2025;15(1):208-229
- CountryChina
- Language:English
-
Abstract:
Radiation-induced thrombocytopenia(RIT)faces a perplexing challenge in the clinical treatment of cancer patients,and current therapeutic approaches are inadequate in the clinical settings.In this research,oxy-matrine,a new molecule capable of healing RIT was screened out,and the underlying regulatory mecha-nism associated with magakaryocyte(MK)differentiation and thrombopoiesis was demonstrated.The capacity of oxymatrine to induce MK differentiation was verified in K-562 and Meg-01 cells in vitro.The ability to induce thrombopoiesis was subsequently demonstrated in Tg(cd41:enhanced green fluorescent protein(eGFP))zebrafish and RIT model mice.In addition,we carried out network pharmacological pre-diction,drug affinity responsive target stability assay(DARTS)and cellular thermal shift assay(CETSA)analyses to explore the potential targets of oxymatrine.Moreover,the pathway underlying the effects of oxymatrine was determined by Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses,Western blot(WB),and immunofluorescence.Oxymatrine markedly promoted MK differentiation and maturation in vitro.Moreover,oxymatrine induced thrombopoiesis in Tg(cd41:eGFP)zebrafish and accelerated thrombopoiesis and platelet function recovery in RIT model mice.Mechanistically,oxymatrine directly binds to toll-like receptor 2(TLR2)and further regulates the downstream pathway stimulator of interferon genes(STING)/nuclear factor-kappaB(NF-κB),which can be blocked by C29 and C-176,which are specific inhibitors of TLR2 and STING,respectively.Taken together,we demonstrated that oxymatrine,a novel TLR2 agonist,plays a critical role in accelerating MK differentiation and thrombopoiesis via the STING/NF-κB axis,suggesting that oxymatrine is a promising candidate for RIT therapy.
