Halofuginone (RU-19110) is a derivative of febrifugine and can inhibit prolyl tRNA synthetase activity, with a Ki value of 18.3nM [1]. Halofuginone can induce pulmonary vasodilation by activating Kv channels and blocking voltage-dependent Ca2+ channels (VDCCs) and receptor-operated and store-operated Ca2+ channels[2]. Halofuginone has been widely used to inhibit collagen synthesis and alleviate liver and lung fibrosis in animals[3].
In vitro, Halofuginone treatment for 24 hours significantly inhibited the proliferation of U937 cells, OCI-AML3 cells and MV4-11 cells, with IC50 values of 0.06μM, 0.05μM and 0.09μM, respectively[4]. The 5nM Halofuginone treatment for 48 hours significantly inhibited the IL-2-mediated cell proliferation in activated mouse T cells and promoted cell apoptosis[5]. Treatment with 100nM Halofuginone for 24 hours significantly reduced the mRNA and protein levels of NRF2 in A549 cells and decreased the expression of NRF2 target genes[6].
In vivo, Halofuginone treatment via intraperitoneal injection at a dose of 1mg/kg every other day for one month significantly alleviated the progression of osteoarthritis in the anterior cruciate ligament transection (ACLT) mouse model, reducing the activity of TGF-β in subchondral bone and abnormal angiogenesis[7]. A weekly five-time intraperitoneal injection of 0.25mg/kg dose of Halofuginone, for a duration of 4 weeks, significantly reduced the tumor volume in mice carrying human-derived uterine lymphoma (UL) xenograft tumors, without altering the mice's body weight[8].
References:
[1] Keller T L, Zocco D, Sundrud M S, et al. Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase[J]. Nature chemical biology, 2012, 8(3): 311-317.
[2] Jain P P, Zhao T, Xiong M, et al. Halofuginone, a promising drug for treatment of pulmonary hypertension[J]. British journal of pharmacology, 2021, 178(17): 3373-3394.
[3] Pines M, Nagler A. Halofuginone: a novel antifibrotic therapy[J]. General Pharmacology: The Vascular System, 1998, 30(4): 445-450.
[4] Shi L, Zhao M, Meng C, et al. Halofuginone exerts broad-spectrum cytotoxic effects by regulating p-eIF2α-S100A8/A9-calcium signaling, inhibiting global protein synthesis, and reversing the resistance of idarubicin in acute myeloid leukemia[J]. Chinese Medicine, 2026, 21(1): 7.
[5] Chu T L H, Guan Q, Nguan C Y C, et al. Halofuginone suppresses T cell proliferation by blocking proline uptake and inducing cell apoptosis[J]. International Immunopharmacology, 2013, 16(4): 414-423.
[6] Tsuchida K, Tsujita T, Hayashi M, et al. Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation[J]. Free Radical Biology and Medicine, 2017, 103: 236-247.
[7] Cui Z, Crane J, Xie H, et al. Halofuginone attenuates osteoarthritis by inhibition of TGF-β activity and H-type vessel formation in subchondral bone[J]. Annals of the rheumatic diseases, 2016, 75(9): 1714-1721.
[8] Koohestani F, Qiang W, MacNeill A L, et al. Halofuginone suppresses growth of human uterine leiomyoma cells in a mouse xenograft model[J]. Human Reproduction, 2016, 31(7): 1540-1551.
Halofuginone (RU-19110)是febrifugine的衍生物，可抑制prolyl tRNA synthetase活性，Ki值为18.3nM[1]。Halofuginone可通过激活Kv通道并阻断电压依赖性Ca2+通道(VDCCs)以及受体介导型和储存介导型Ca2+通道，诱导肺血管舒张[2]。Halofuginone已被广泛用于抑制胶原合成，并减轻动物的肝脏和肺纤维化[3]。
在体外，Halofuginone处理24小时显著抑制了U937细胞、OCI-AML3细胞和MV4-11细胞的增殖，IC50值分别为0.06μM、0.05μM和0.09μM[4]。5nM的Halofuginone处理48小时显著抑制了活化小鼠T细胞中IL-2介导的细胞增殖，并促进了细胞凋亡[5]。使用100nM的Halofuginone处理A549细胞24小时，显著降低了NRF2的mRNA和蛋白水平，同时也降低了NRF2靶基因的表达[6]。
在体内，每隔一天腹腔注射1mg/kg剂量的Halofuginone，持续一个月，显著减轻了前交叉韧带横断(ACLT)小鼠模型中骨关节炎的进展，降低了软骨下骨中TGF-β的活性和异常血管生成[7]。每周五次腹腔注射0.25mg/kg剂量的Halofuginone，持续4周，显著减小了携带人源性子宫淋巴瘤(UL)异种移植瘤小鼠的肿瘤体积，且未改变小鼠的体重[8]。