Nrf2-IN-1 is an inhibitor of nuclear factor-erythroid 2-related factor 2 (Nrf2), which is developed for the research of acute myeloid leukemia (AML) [1]. Nrf2-IN-1 inhibited the expression of Nrf2/HO-1/NQO1 pathway-related proteins as well as that of the ferroptosis resistance-related proteins GPX4, SLC7A11, and FTH1[2]. Nrf2-IN-1 has been widely used to regulate oxidative stress in models of myocardial ischemia-reperfusion injury[3].
In vitro, Nrf2-IN-1 treatment for 48 hours significantly inhibited the viability of THP-1 cells, HL-60 cells, and U937 cells, with IC50 values of 5.33µM, 8.94µM, and 8.98µM, respectively[4]. Treatment of microglial cells with 5µM Nrf2-IN-1 for 48 hours significantly inhibited the interaction between Nrf2 and ACOD1 and reduced the expression of ACOD1[5]. Treatment with 10µM Nrf2-IN-1 for 24 hours significantly reduced the expression levels of ADAM8 and Nrf2 in HT22 cells induced by Erastin, promoted the production of reactive oxygen species (ROS), and increased cell death[6].
In vivo, Nrf2-IN-1 treatment via intraperitoneal injection at a dose of 10µmol/kg/day for 7 days counteracted the neuroprotective effect of shRIN1 in the rat model of chronic constriction injury (CCI), significantly increased the Fe2+ level in spinal cord tissue, accompanied by severe mitochondrial damage[7]. Twelve hours before establishing the cecum ligation perforation (CLP) model, intraperitoneal injection of a single dose of Nrf2-IN-1 (10mg/kg) in mice significantly inhibited the protective effect of Klotho on the kidneys and promoted kidney damage[8].
References:
[1] Han Y, Gao X, Wu N, et al. Long noncoding RNA LINC00239 inhibits ferroptosis in colorectal cancer by binding to Keap1 to stabilize Nrf2[J]. Cell death & disease, 2022, 13(8): 742.
[2] Du L, Zhu X, Jiang Z, et al. Resveratrol inhibits ferroptosis in the lung tissues of heat stroke-induced rats via the Nrf2 pathway[J]. BMC Pharmacology and Toxicology, 2024, 25(1): 88.
[3] Li W, Yu W, Xu W, et al. Death-associated protein kinase 1 regulates oxidative stress in cardiac ischemia reperfusion injury[J]. Cells Tissues Organs, 2021, 210(5-6): 380-390.
[4] Zhang J F, Su L, Ye Q, et al. Discovery of a novel Nrf2 inhibitor that induces apoptosis of human acute myeloid leukemia cells[J]. Oncotarget, 2016, 8(5): 7625.
[5] Qian Z, Xia M, Zhao T, et al. ACOD1, rather than itaconate, facilitates p62‐mediated activation of Nrf2 in microglia post spinal cord contusion[J]. Clinical and Translational Medicine, 2024, 14(4): e1661.
[6] Qian Z, Zhang Q, Li P, et al. A disintegrin and metalloproteinase-8 protects against erastin-induced neuronal ferroptosis via activating nrf2/ho-1/fth1 signaling pathway[J]. Molecular Neurobiology, 2024, 61(6): 3490-3502.
[7] Lin X, Li X, Hong S, et al. RIN1 regulates ferroptosis and nociceptive perception via the Nrf2/HO-1 pathway in chronic constriction injury[J]. Cellular Signalling, 2025, 132: 111784.
[8] Zhou P, Zhao C, Chen Y, et al. Klotho activation of Nrf2 inhibits the ferroptosis signaling pathway to ameliorate sepsis-associated acute kidney injury[J]. Translational andrology and urology, 2023, 12(12): 1871.
Nrf2-IN-1是nuclear factor-erythroid 2-related factor 2 (Nrf2)的抑制剂，用于急性髓系白血病(AML)的研究[1]。Nrf2-IN-1抑制Nrf2/HO-1/NQO1通路相关蛋白以及铁死亡抵抗相关蛋白GPX4、SLC7A11和FTH1 的表达[2]。Nrf2-IN-1已被广泛用于调节心肌缺血再灌注损伤模型中的氧化应激[3]。
在体外，Nrf2-IN-1处理48小时显著抑制了THP-1细胞、HL-60细胞和U937细胞的活力，IC50值分别为5.33μM、8.94μM和8.98μM[4]。用5μM的Nrf2-IN-1处理小胶质细胞48小时，显著抑制了Nrf2与 ACOD1之间的相互作用，并降低了ACOD1的表达[5]。用10μM的Nrf2-IN-1处理HT22细胞24小时，显著降低了Erastin诱导的ADAM8和Nrf2表达水平，促进了活性氧(ROS)的产生，并促进了细胞死亡[6]。
在体外，在慢性压迫性损伤大鼠模型中，腹腔注射10μmol/kg/day剂量的Nrf2-IN-1连续7天，抵消了 shRIN1的神经保护作用，显著增加了脊髓组织中的Fe2+水平，并伴有严重的线粒体损伤[7]。在建立盲肠结扎穿孔(CLP)模型前12小时，单次腹腔注射10mg/kg剂量的Nrf2-IN-1，显著抑制了Klotho对小鼠肾脏的保护作用，并促进了肾损伤[8]。