Artemisinin derived from Artemisia annua L. promotes thrombopoiesis via targeting FLT3: a novel strategy for thrombocytopenia management

i

This article has been updated. A Correction to this article was published on .

i

The Original Article was published on

i

The Original Article was published on

i

This article has been updated

i

This article was retracted on

i

This article has been updated

Abstract

Artemisia annua L. (A. annua) has long been documented in traditional Chinese medicine for managing hemorrhagic conditions, attributed to its cooling and hemostatic properties. These historical applications suggest a potential role of A. annua in platelet-related disorders, although its hematopoietic mechanisms remain unclear. To investigate the thrombopoietic activity of A. annua, identify its bioactive constituent, and elucidate the molecular mechanisms underlying its effects on thrombopoiesis. Chemical profiling identified major compounds in A. annua. MK differentiation was assessed in K562, Meg-01 cells, and primary murine haematopoietic stem and progenitor cells (HSPCs). A murine radiation-induced thrombocytopenia (RIT) model was used to evaluatein vivo efficacy. Molecular docking, drug affinity responsive target stability (DARTS), and signaling assays were conducted to explore molecular mechanisms. A. annua promoted MK differentiation, upregulating CD41/CD42b and enhancing polyploidization. Artemisinin was identified as the principal active compound. It promoted MK maturation in vitro and restored platelet counts, MK numbers, and HSPC populations in RIT mice without inducing systemic toxicity. Artemisinin also reduced bone marrow (BM) apoptosis and DNA damage while restoring platelet function. Mechanistically, artemisinin directly bound to FLT3 and activated the FLT3/MAPK pathway, leading to increased phosphorylation of MEK/ERK and upregulation of NF-E2 and TAL1. FLT3 and ERK inhibition abrogated these effects. Artemisinin is a potent thrombopoietic agent that acts via direct activation of FLT3 and its downstream MAPK signaling cascade. The findings identify FLT3 as a novel therapeutic target for thrombocytopenia and support the potential clinical application of artemisinin in radiation-related hematological disorders.

Keywords

Artemisia annua L / Artemisinin / Megakaryocyte differentiation / Thrombocytopenia / FLT3

CHANGE HISTORY

A Correction to this paper has been published:
https://doi.org

The Retraction Note was updated to reflect reception of statements of disagreement from all authors.

This article has been retracted.Please see the Retraction Notice for more detail:
https://doi.org

References

[1] Guo H, Chou WC, Lai Y, et al. Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites. Science. 2020; 370(6516):eaay9097. https://doi.org/10.1126/science.aay9097.

[2] Zhang L, Xu W, Zeng Y, et al. Astragaloside IV accelerates hematopoietic reconstruction by improving the AMPK/PGC1α-mediated mitochondrial function in hematopoietic stem cells. Chin Med. 2025; 20(1):44. https://doi.org/10.1186/s13020-025-01092-3.

[3] Huang M, Ye A, Zhang H, et al. Siwu Decoction mitigates radiation-induced immune senescence by attenuating hematopoietic damage. Chin Med. 2024; 19(1):167. https://doi.org/10.1186/s13020-024-01036-3.

[4] Xu Y, Wang S, Shen MQ, et al. hGH promotes megakaryocyte differentiation and exerts a complementary effect with c-Mpl ligands on thrombopoiesis. Blood. 2014; 123(14):2250-2260. https://doi.org/10.1182/blood-2013-09-525402.

[5] Singh VK, Seed TM . Pharmacological management of ionizing radiation injuries: current and prospective agents and targeted organ systems. Expert Opin Pharmacother. 2020; 21(3):317-337. https://doi.org/10.1080/14656566.2019.1702968.

[6] Furniss JA, Tarassova N, Poole AWJB . Platelet generation in vivo and in vitro. Blood. 2024; 144(22):2283-2294. https://doi.org/10.1182/blood.2024024601.

[7] Eto K, Kunishima S . Linkage between the mechanisms of thrombocytopenia and thrombopoiesis. Blood. 2016; 127(10):1234-1241. https://doi.org/10.1182/blood-2015-07-607903.

[8] Bianchi E, Norfo R, Pennucci V, et al. Genomic landscape of megakaryopoiesis and platelet function defects. Blood. 2016; 127(10):1249-1259. https://doi.org/10.1182/blood-2015-07-607952.

[9] Noetzli LJ, French SL, Machlus KR . New insights into the differentiation of megakaryocytes from hematopoietic progenitors. Arterioscler Thromb Vasc Biol. 2019; 39(7):1288-1300. https://doi.org/10.1161/ATVBAHA.119.312129.

[10] Machlus KR, Johnson KE, Kulenthirarajan R, et al. CCL5 derived from platelets increases megakaryocyte proplatelet formation. Blood. 2016; 127(7):921-926. https://doi.org/10.1182/blood-2015-05-644583.

[11] Yang F, Lai J, Deng J, et al. The application of ethnomedicine in modulating megakaryocyte differentiation and platelet counts. Int J Mol Sci. 2023; 24(4):3168. https://doi.org/10.3390/ijms24043168.

[12] Chen W, Zhu LJ, Wang L, et al. A novel antithrombocytopenia agent, Rhizoma Cibotii, promotes megakaryopoiesis and thrombopoiesis through the PI3K/AKT, MEK/ERK, and JAK2/STAT3 signaling pathways. Int J Mol Sci. 2022; 23(22):14060. https://doi.org/10.3390/ijms232214060.

[13] Yang X, Wang L, Zeng J, et al. Caulis polygoni multiflori accelerates megakaryopoiesis and thrombopoiesis via activating PI3K/akt and MEK/ERK signaling pathways. Pharmaceuticals (Basel). 2022; 15(10):1204. https://doi.org/10.3390/ph15101204.

[14] Ming HL, Wen HL, Ming QH . Professor Qiu Heming's case study on treating blood diseases with Artemisia annua and Biejia Decoction. J New Chin Med. 2004; 36(7):27-28. https://doi.org/10.3969/j.issn.0256-7415.2004.07.003.

[15] Luo W. Clinical experience of modified Artemisia annua and Biejia Decoction in the treatment of hematological diseases. J Pract Tradit Chin Med. 2007; 23(9):7-8. https://doi.org/10.3969/j.issn.1004-2814.2007.09.048.

[16] Gong J. The anti-leukemia effect of artemisinin and its derivatives. Int J Blood Transfus Hematol. 2007; 30(3):264-266. https://doi.org/10.3760/cma.j.issn.1673-419X.2007.03.017.

[17] Wang BC, Sui J, Yu ZW, et al. Screening the hemostatic active fraction of Artemisia annua L. in-vitro. Iran J Pharm Res. 2011; 10(1):57.

[18] Huang ZY, Fan B, Mao WW, et al. Topical application of Artemisia annua L. essential oil ameliorates 2, 4-dintrochlorobenzene-induced atopic dermatitis in mice. J Ethnopharmacol. 2024; 333:118439. https://doi.org/10.1016/j.jep.2024.118439.

[19] Zhao XW, Dai X, Wang FY, et al. Artemisia annua L. leaf extracts suppress influenza virus infection by targeting the viral nucleoprotein and blocking mitochondria-mediated apoptosis. Virol Sin. 2025; 40(2):247-59. https://doi.org/10.1016/j.virs.2025.03.001.

[20] Liang D, Xuan DY, Liu Chang, et al. Mechanism of Artemisia annua L. in the treatment of acute myocardial infarction: network pharmacology, molecular docking and in vivo validation. Mol Divers. 2024; 28:3225-3342. https://doi.org/10.1007/s11030-023-10750-3.

[21] Gao P, Wang JY, Qiu C, et al. Photoaffinity probe-based antimalarial target identification of artemisinin in the intraerythrocytic developmental cycle of Plasmodium falciparum. iMeta. 2024; 3(2):e176. https://doi.org/10.1002/imt2.176.

[22] Lim HS, Park G . Artemisinin protects dopaminergic neurons against 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced neurotoxicity in a mouse model of Parkinson’s disease. Biomed Pharmacother. 2024; 170:115972. https://doi.org/10.1016/j.biopha.2023.115972.

[23] Liu Y, Jiang JJ, Du SY, et al. Artemisinins ameliorate polycystic ovarian syndrome by mediating LONP1-CYP11A1 interaction. Science. 2024; 384(6701):eadk5382. https://doi.org/10.1126/science.adk5382.

[24] Wang L, Liu S, Luo JS, et al. Targeting a thrombopoietin-independent strategy in the discovery of a novel inducer of megakaryocytopoiesis, DMAG, for the treatment of thrombocytopenia. Haematologica. 2022; 108(5):1394. https://doi.org/10.3324/haematol.2022.282209.

[25] Wang L, Zhang T, Yang X, et al. Multimodal discovery of bavachinin A: a natural FLT3 agonist for treating thrombocytopenia. Phytomedicine. 2025; 140:156597. https://doi.org/10.1016/j.phymed.2025.156597.

[26] Tang XQ, Liao R, Zhou L, et al. Genistin: a novel estrogen analogue targeting ERβ to alleviate thrombocytopenia. Int J Biol Sci. 2024; 20(6):2236. https://doi.org/10.7150/ijbs.90483.

[27] Huang M, Wang L, Zhang QH, et al. Interleukins in platelet biology: unraveling the complex regulatory network. Pharmaceuticals (Basel). 2024; 17(1):109. https://doi.org/10.3390/ph17010109.

[28] Chu SH, Heiser D, Li L, et al. FLT3-ITD knockin impairs hematopoietic stem cell quiescence/homeostasis, leading to myeloproliferative neoplasm. Cell Stem Cell. 2012; 11(3):346-358. https://doi.org/10.1016/j.stem.2012.05.027.

[29] Stirewalt DL, Radich JP . The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003; 3:650-665. https://doi.org/10.1038/nrc1169.

[30] Tkaczynski E, Arulselvan A, Tkaczynski J, et al. 2-O, 3-O desulfated heparin mitigates murine chemotherapy-and radiation-induced thrombocytopenia. Blood Adv.. 2018; 2(7):754-761. https://doi.org/10.1182/bloodadvances.2017013672.

[31] Barazzuol L, Coppes RP, Luijk Pv . Prevention and treatment of radiotherapy-induced side effects. Mol Oncol. 2020; 14(7):1538-1554. https://doi.org/10.1002/1878-0261.12750.

[32] Ghanima W, Cooper N, Rodeghiero F, et al. Thrombopoietin receptor agonists: ten years later. Haematologica. 2019; 104(6):1112. https://doi.org/10.3324/haematol.2018.212845.

[33] Poston JN, Gernsheimer TB . Glucocorticoids promote response to thrombopoietin-receptor agonists in refractory ITP: a case series. Int J Hematol. 2019; 110(2):255-259. https://doi.org/10.1007/s12185-019-02638-6.

[34] Catalá-López F, Corrales I, de la Fuente-Honrubia C, et al. Risk of thromboembolism with thrombopoietin receptor agonists in adult patients with thrombocytopenia: systematic review and meta-analysis of randomized controlled trials. Med Clin (Barc). 2015; 145(12):511-519. https://doi.org/10.1016/j.medcli.2015.03.014.

[35] Liu YQ, Wang XL, He DH, et al. Protection against chemotherapy-and radiotherapy-induced side effects: a review based on the mechanisms and therapeutic opportunities of phytochemicals. Phytomedicine. 2021; 80:153402. https://doi.org/10.1016/j.phymed.2020.153402.

[36] Du C, Xu Y, Yang K, et al. Estrogen promotes megakaryocyte polyploidization via estrogen receptor beta-mediated transcription of GATA1. Leukemia. 2017; 31(4):945-956. https://doi.org/10.1038/leu.2016.285.

[37] Jiang XQ, Sun YS, Yang S, et al. Novel chemical-structure TPOR agonist, TMEA, promotes megakaryocytes differentiation and thrombopoiesis via mTOR and ERK signalings. Phytomedicine. 2023; 110:154637. https://doi.org/10.1016/j.phymed.2022.154637.

[38] Yang S, Wang L, Wu YS, et al. Apoptosis in megakaryocytes: safeguard and threat for thrombopoiesis. Front Immunol. 2023; 13:1025945. https://doi.org/10.3389/fimmu.2022.1025945.

[39] Sekikawa Y, Kato TA. Radiation-induced Gamma-H2AX foci staining and analysis. In: TA Kato, eds. DNA damage detection: methods and protocols. New York, NY:Humana Press; 2025:25-29. https://doi.org/10.1007/978-1-0716-4574-1_4.

[40] Behrens K, Alexander WS . Cytokine control of megakaryopoiesis. Growth Factors. 2018; 36(3-4):89-103. https://doi.org/10.1080/08977194.2018.1498487.

[41] Sun SJ, Wang WJ, Latchman Y, et al. Expression of plasma membrane receptor genes during megakaryocyte development. Physiol Genomics. 2013; 45(6):217-227. https://doi.org/10.1152/physiolgenomics.00056.2012.

[42] Chen X, Wang YT, Ma N, et al. Target identification of natural medicine with chemical proteomics approach: probe synthesis, target fishing and protein identification. Signal Transduct Target Ther.. 2020; 5(1):72. https://doi.org/10.1038/s41392-020-0186-y.