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.