Noscapine derivative 428 suppresses ferroptosis through targeting GPX4
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.
Authors
- Ligen Liu (ORCID: https://orcid.org/0000-0002-3971-783X)
- Hu Lei (ORCID: https://orcid.org/0000-0003-3288-5205)
- Haoliang Shi (ORCID: https://orcid.org/0009-0000-1200-455X)
- Wan-Ting Liu (ORCID: https://orcid.org/0000-0002-0378-255X)
- Hanzhang Xu (ORCID: https://orcid.org/0000-0001-6600-7756)
- G. Li (ORCID: https://orcid.org/0009-0008-5434-1923)
- Wenhui Bai
- Youping Zhang (ORCID: https://orcid.org/0000-0002-6098-8634)
- Yanjie Ji (ORCID: https://orcid.org/0000-0002-7172-3818)
- Yongqiang Zhang (ORCID: https://orcid.org/0000-0003-1403-9128)
- Yunzhao Wu (ORCID: https://orcid.org/0000-0002-5792-7494)
- Wenxuan Wu (ORCID: https://orcid.org/0000-0003-2308-7949)
- Yingying Wang (ORCID: https://orcid.org/0000-0002-0603-6691)
- Wei Wang
- Ziwei Zhang (ORCID: https://orcid.org/0000-0002-5705-4611)
- Li Yang (ORCID: https://orcid.org/0000-0003-0754-7941)
- Baohui Han (ORCID: https://orcid.org/0000-0002-6251-3771)
- Defeng Li (ORCID: https://orcid.org/0000-0003-3118-6840)
- Yaxue Zhao (ORCID: https://orcid.org/0000-0002-5963-9779)
- Yingli Wu
- Chujiao Zhu
- Hua Zhong (ORCID: https://orcid.org/0000-0003-3097-5717)
Institutions
- University of Arizona (US)
- East China University of Science and Technology (CN)
- Shanghai Jiao Tong University (CN)
- University of Cambridge (GB)
- Shanghai Chest Hospital (CN)
- Tongren Hospital (CN)
- Ministry of Education (TH)
Publication Details
- Journal
- Redox Biology
- Published
- 2025-04-12
- DOI
- https://doi.org/10.1016/j.redox.2025.103635
- Citations
- 4
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 6.07
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation