Most BTB-containing E3 ligases homodimerize to recognize a single substrate by engaging multiple degrons, represented by E3 ligase KEAP1 dimer and its substrate NRF2. Inactivating KEAP1 to hinder ubiquitination-dependent NRF2 degradation activates NRF2. While various KEAP1 inhibitors have been reported, all reported inhibitors bind to KEAP1 in a monovalent fashion and activate NRF2 in a lagging manner. Herein, we report a unique bivalent KEAP1 inhibitor, biKEAP1 (), that engages cellular KEAP1 dimer to directly release sequestered NRF2 protein, leading to an instant NRF2 activation. promotes the nuclear translocation of NRF2, directly suppressing proinflammatory cytokine transcription. Data from experiments showed that , with unprecedented potency, reduced acute inflammatory burden in several acute inflammation models in a timely manner. Our findings demonstrate that the bivalent KEAP1 inhibitor can directly enable sequestered substrate NRF2 to suppress inflammatory transcription response and dampen various acute inflammation injuries.

中文翻译：

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BTB E3 连接酶 KEAP1 的二价抑制剂能够立即激活 NRF2，从而抑制急性炎症反应

大多数含有 BTB 的 E3 连接酶均二聚化，通过接合多个降解决定子（以 E3 连接酶 KEAP1 二聚体及其底物 NRF2 为代表）来识别单个底物。失活 KEAP1 以阻止泛素化依赖性 NRF2 降解，从而激活 NRF2。虽然已报道了各种 KEAP1 抑制剂，但所有报道的抑制剂均以单价方式与 KEAP1 结合，并以滞后方式激活 NRF2。在此，我们报告了一种独特的二价 KEAP1 抑制剂 biKEAP1 ()，它与细胞 KEAP1 二聚体结合，直接释放隔离的 NRF2 蛋白，导致 NRF2 即时激活。促进 NRF2 的核转位，直接抑制促炎细胞因子转录。实验数据表明，以前所未有的效力，及时减轻了几种急性炎症模型中的急性炎症负担。我们的研究结果表明，二价 KEAP1 抑制剂可以直接使隔离底物 NRF2 抑制炎症转录反应并减轻各种急性炎症损伤。