Noscapine derivative 428 suppresses ferroptosis through targeting GPX4

作者：Youping Zhang, Haoliang Shi, Yingying Wang, Wan-Ting Liu, G. Li, Defeng Li, Wenxuan Wu, Yunzhao Wu, Ziwei Zhang, Yanjie Ji, Chujiao Zhu, Wenhui Bai, Hu Lei, Hanzhang Xu, Hua Zhong, Baohui Han, Li Yang, Ligen Liu, Wei Wang, Yaxue Zhao, Yongqiang Zhang, Yingli Wu · 发表于：Redox Biology · 年份：2025 · DOI：10.1016/j.redox.2025.103635 · 被引用次数：5 · 研究领域：Ferroptosis and cancer prognosis、RNA modifications and cancer、Cancer-related molecular mechanisms research

Inhibiting ferroptosis represents a promising strategy to combat ferroptosis-related diseases. Here we show that 428 , a selenide-containing noscapine derivative, effectively inhibits ferroptosis in various cell lines by enhancing the stability and activity of GPX4. TRIM41 was identified as a novel E3 ubiquitin ligase of GPX4 and 428 was demonstrated to bind to the selenocysteine residue Sec46 of GPX4 via the formation of a transient and reversible Se–Se bond, thereby blocking the interaction between GPX4 and TRIM41, stabilizing GPX4 and enhancing its activity. This unique dynamic covalent binding mode was preliminarily validated by structure-activity relationship analysis and molecular docking studies. Importantly, we demonstrated that 428 treatment alleviates bleomycin-induced pulmonary fibrosis in vivo by inhibiting ferroptosis. Overall, our studies identified a novel stabilizer and activator of GPX4, offering a potential therapeutic approach for the treatment of ferroptosis-related diseases and uncovering a new mechanism for regulating GPX4 degradation. Ferroptosis is involved in idiopathic pulmonary fibrosis (IPF) which is characterized by reduced GPX4 and increased lipid ROS accumulation. Noscapine derivative 428 inhibits ferroptosis by stabilizing and activating GPX4. 428 directly interacts with GPX4 and blocks the interaction between GPX4 and TRIM41, a newly-identified E3 ubiquitin ligase responsible for GPX4 degradation, thereby stabilizing GPX4 protein level. 428 si...