Discovery of a novel chalcone-derived covalent Keap1 binder for mitigating cisplatin-induced mitochondrial dysfunction and nephrotoxicity

作者：Yanyan Deng, Lang Xu, Zhengtao Jiang, Lin Chen, Guanghao Zhu, C. Xu, Xiayan Chu, Lixin Wang, Xiaoting Niu, Ling Chen, Zhangping Xiao, Jing Hu, Guang‐Bo Ge · 发表于：Redox Biology · 年份：2025 · DOI：10.1016/j.redox.2025.103737 · 被引用次数：15 · 研究领域：Chemotherapy-induced organ toxicity mitigation、Metal complexes synthesis and properties、Pharmacological Effects and Toxicity Studies

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, ...