Bardoxolone methyl is an effective activator of the antioxidant and anti-inflammatory response mediated by nuclear factor erythroid 2-related factor 2 (Nrf2), and it is also an inhibitor of the NF-κB pathway [1]. Nrf2 is a transcription factor, a basic leucine zipper (bZIP) protein, which regulates the expression of antioxidant proteins. These antioxidant proteins can prevent oxidative damage caused by damage and inflammation [2]. Bardoxolone methyl can inhibit ferroptosis and induce apoptosis and autophagy in cancer cells. Bardoxolone methyl has been used to treat chronic kidney disease, cancer (including leukemia and solid tumors), and other diseases [3-4].
In vitro, Bardoxolone methyl (0.3, 1.0μM; 4h) significantly reduced mitochondrial damage induced by paclitaxel in 50B11 cells, reversed the reduction in mitochondrial membrane potential (MMP) and the increase in mitochondrial volume induced by paclitaxel, and significantly increased the intensity of pNrf2 in the cells [5]. Bardoxolone methyl (5μM; 72h) significantly reduced the cell viability of leukemia cells (HL-60, KG-1, and NB4 cells) with IC50 values of 0.4, 0.4, and 0.27μM, respectively [6].
In vivo, Bardoxolone methyl (5, 10mg/kg; single dose; oral gavage) alleviated oxidative stress, histopathological damage, and cell apoptosis in the kidneys of rats with acetaminophen-induced acute kidney injury in a dose-dependent manner, and also reduced the expression of KIM-1, NGAL, and TNF-α in the kidneys [7]. Bardoxolone methyl (1, 3, 10mg/kg; twice a day, 4d; i.p.) significantly improved neuropathic pain induced by paclitaxel in rats, increased the expression of pNRf2 and HO-1 in the lumbar dorsal root ganglion (DRG), and reduced the levels of pNFκB and MCP-1 [5].
References:
[1] Reisman SA, Chertow GM, Hebbar S, Vaziri ND, Ward KW, Meyer CJ. Bardoxolone methyl decreases megalin and activates nrf2 in the kidney. J Am Soc Nephrol. 2012;23(10):1663-1673.
[2] Bellezza I, Giambanco I, Minelli A, Donato R. Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim Biophys Acta Mol Cell Res. 2018;1865(5):721-733.
[3] Schiavoni V, Di Crescenzo T, Membrino V, et al. Bardoxolone Methyl: A Comprehensive Review of Its Role as a Nrf2 Activator in Anticancer Therapeutic Applications[J]. Pharmaceuticals, 2025, 18(7): 966.
[4] Wang Y Y, Yang Y X, Zhe H, et al. Bardoxolone methyl (CDDO-Me) as a therapeutic agent: an update on its pharmacokinetic and pharmacodynamic properties[J]. Drug design, development and therapy, 2014: 2075-2088.
[5] Kim HK, Wang Q, Hwang SH, Dougherty PM, Wang J, Abdi S. Bardoxolone Methyl Ameliorates Chemotherapy-Induced Neuropathic Pain by Activation of Phosphorylated Nuclear Factor Erythroid 2-Related Factor 2 in the Dorsal Root Ganglia. Anesth Analg. 2024;138(3):664-675.
[6] Konopleva M, Tsao T, Ruvolo P, Stiouf I, Estrov Z, Leysath CE, Zhao S, Harris D, Chang S, Jackson CE, Munsell M, Suh N, Gribble G, Honda T, May WS, Sporn MB, Andreeff M. Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia. Blood. 2002 Jan 1;99(1):326-35.
[7] Teksen Y, Kadıoglu E, Ozatik F Y, et al. Bardoxolone methyl attenuates acetaminophen-induced acute kidney injury by suppressing oxidative stress, inflammation and apoptosis[J]. 2024.
Bardoxolone methyl是核因子红细胞2相关因子2（Nrf2）介导的抗氧化和抗炎反应的有效激活剂，也是NF-κB通路的抑制剂 [1]。Nrf2是一种转录因子，是一种碱性亮氨酸拉链（bZIP）蛋白，它调节抗氧化蛋白的表达，这些抗氧化蛋白可以防止损伤和炎症引起的氧化损伤 [2]。Bardoxolone Methyl可抑制铁死亡并在癌细胞中诱导凋亡和自噬。Bardoxolone methyl已用于治疗慢性肾脏病、癌症（包括白血病和实体瘤）和其他疾病 [3-4]。
在体外，Bardoxolone methyl（0.3,1.0μM; 4h）显著减少了紫杉醇诱导的50B11细胞线粒体损伤，逆转了紫杉醇诱导的线粒体膜电位（MMP）降低和线粒体体积增加，并显著增加了细胞中pNrf2的强度 [5]。Bardoxolone methyl（5μM; 72h）显著降低了白血病细胞（HL-60、KG-1和NB4细胞）的细胞活力，其IC50值分别为0.4、0.4和0.27μM [6]。
在体内，Bardoxolone methyl (5, 10mg/kg; single dose; oral gavage)以剂量依赖性的方式缓解了乙酰氨基酚诱导的急性肾损伤大鼠肾脏的氧化应激、组织病理损伤和细胞凋亡，还降低了肾脏中的KIM-1、NGAL和TNF-α的表达 [7]。Bardoxolone methyl（1, 3, 10mg/kg; twice a day, 4d; i.p.）显著改善了紫杉醇诱导的大鼠的神经性疼痛，增加了腰段背根神经节（DRG）中pNRf2和HO-1的表达，降低了pNFκB和MCP-1水平 [5]。