Deng Yanyan, Xu Leizhi, Jiang Zhengtao, Chen Lin, Zhu Guanghao, Xu Chuting, Chu Xiayan, Wang Lixin, Niu Xiaoting, Chen Ling, Xiao Zhangping, Hu Jing, Ge Guangbo
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Department of Nephropathy, The Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China.
Redox Biol. 2025 Jun 21;85:103737. doi: 10.1016/j.redox.2025.103737.
Cisplatin-induced kidney injury (CIKI) is a major adverse effect of this widely used chemotherapy agent. Targeting key events involved in CIKI, such as inflammation, apoptosis, mitochondrial dysfunction and oxidative stress, holds potential for mitigating CIKI and improving patient outcomes. Herein, we report a novel N-containing chalcone derivative as a cysteine-targeting covalent binder of Keap1, which effectively mitigate cisplatin (CDDP)-induced mitochondrial dysfunction (CIMD) and CIKI through activating Keap1-Nrf2-ARE signaling. Initially, a chalcone derivative (A6) was identified as a strong Nrf2 agonist through high-throughput luminescence screening of in-house compounds. After two rounds of structural optimization, we developed a novel N-containing chalcone derivative (C5), which exhibits enhanced Nrf2 agonist activity, favorable drug-like properties, and improved renal-targeting ability. Cellular and animal studies showed that C5 significantly ameliorated CIMD and CIKI in CDDP-induced nephrocytes and CIKI mice via activating the Keap1-Nrf2-ARE signaling pathway in both settings. Mechanistically, C5 covalently modified Keap1 on two critical functional cysteines in Keap1 (Cys288 in the IVR domain and Cys319 in the Kelch domain), synergistically amplifying Nrf2 activation. As an extremely potent Nrf2 agonist, C5 mitigated CIKI by orchestrating antioxidant defenses, boosting mitochondrial energetics, promoting mitochondrial biogenesis, restoring mitochondrial dynamics, and inhibiting subsequent apoptotic cascade activation. Furthermore, Nrf2 knockdown markedly attenuated the nephroprotective effects of C5 in CIKI mice, confirming the critical role of Keap1-Nrf2 signaling in its nephroprotective mechanism. Collectively, a novel N-containing chalcone derivative was developed as an efficacious and renal-targeting covalent binder of Keap1, offering a promising therapeutic candidate for combating CIKI.
顺铂诱导的肾损伤（CIKI）是这种广泛使用的化疗药物的主要不良反应。针对CIKI中涉及的关键事件，如炎症、细胞凋亡、线粒体功能障碍和氧化应激，有望减轻CIKI并改善患者预后。在此，我们报告一种新型含氮查尔酮衍生物，它是一种靶向半胱氨酸的Keap1共价结合剂，通过激活Keap1-Nrf2-ARE信号通路有效减轻顺铂（CDDP）诱导的线粒体功能障碍（CIMD）和CIKI。最初，通过对内部化合物进行高通量发光筛选，鉴定出一种查尔酮衍生物（A6）为强效Nrf2激动剂。经过两轮结构优化，我们开发了一种新型含氮查尔酮衍生物（C5），它具有增强的Nrf2激动剂活性、良好的类药性质和改善的肾脏靶向能力。细胞和动物研究表明，C5通过在两种情况下激活Keap1-Nrf2-ARE信号通路，显著改善了CDDP诱导的肾细胞中的CIMD和CIKI以及CIKI小鼠的症状。从机制上讲，C5在Keap1的两个关键功能半胱氨酸（IVR结构域中的Cys288和Kelch结构域中的Cys319）上共价修饰Keap1，协同放大Nrf2激活。作为一种极其有效的Nrf2激动剂，C5通过协调抗氧化防御、增强线粒体能量代谢、促进线粒体生物发生、恢复线粒体动力学以及抑制随后的凋亡级联激活来减轻CIKI。此外，Nrf2基因敲低显著减弱了C5对CIKI小鼠的肾保护作用，证实了Keap1-Nrf2信号在其肾保护机制中的关键作用。总的来说，一种新型含氮查尔酮衍生物被开发为一种有效且具有肾脏靶向性的Keap1共价结合剂，为对抗CIKI提供了一个有前景的治疗候选物。
