Dipyridamole Acts as Clinical Ferroptosis Inhibitor to Prevent from Tissue Injury
Ferroptosis is a newly identified cell death triggered by iron-induced lipid peroxidation. Numerous studies reveal that ferroptosis participates in multiple types of tissue injury including ischaemia-reperfusion (I/R) injury and doxorubicin (Dox)-induced damage. Targeting ferroptosis is a promising approach for disease treatment as the blockade of ferroptosis efficiently alleviates the symptoms. However, no known ferroptosis inhibitors have been used for clinical treatment. Although certain clinical compounds act as ferroptosis inhibitors in vitro, whether these drugs cure tissue injury by suppressing ferroptosis is little known. Here, by screening a large panel of drugs used in the clinic, it is identified that dipyridamole significantly attenuates Dox or I/R-induced cardiac injury. Moreover, dipyridamole can achieve a good therapeutic effect on liver and kidney injury. Mechanistically, dipyridamole-mediated ferroptosis inhibition is strictly dependent on solute carrier family 7 member 11 (SLC7A11). Dipyridamole down-regulates the expression of ring finger protein 126 (RNF126), which is an E3 ligase to ubiquitinate SLC7A11 for proteasome degradation. Deficiency of SLC7A11 largely blocks the protective role of dipyridamole in vitro and in vivo. Together, the findings uncover that dipyridamole acts as a clinical compound to alleviate organ injury via suppressing ferroptosis, providing novel insights into the clinical therapy for ferroptosis-related tissue damage.
Authors
- Bo Chu (ORCID: https://orcid.org/0000-0001-9754-2743)
- Yinghong Yang
- Huaxiang Yu
- Chengqian Yin (ORCID: https://orcid.org/0000-0003-4247-6245)
- Yang Shu (ORCID: https://orcid.org/0000-0002-8304-1531)
- Junxia Min (ORCID: https://orcid.org/0000-0001-8099-6327)
- Hui Wang (ORCID: https://orcid.org/0000-0002-1119-5849)
- Yong Nian (ORCID: https://orcid.org/0009-0000-2571-696X)
- Yiming Liu (ORCID: https://orcid.org/0000-0001-7200-7197)
- Qi Sun
- Jian Li (ORCID: https://orcid.org/0000-0001-8783-6000)
- Li Yang (ORCID: https://orcid.org/0000-0003-0754-7941)
- Fudi Wang (ORCID: https://orcid.org/0000-0001-8730-0003)
- Lutao Du (ORCID: https://orcid.org/0000-0002-5097-9814)
- Xiao Zhuang
- Bin Huang (ORCID: https://orcid.org/0000-0002-0944-7648)
- Chunhui Liang (ORCID: https://orcid.org/0000-0002-0476-2286)
- Dandan Song (ORCID: https://orcid.org/0000-0003-3766-9237)
- Shuang Shi (ORCID: https://orcid.org/0000-0002-6842-6492)
- Yaqiong Jiao
- Dan Zou
- Xinquan Yang
- Shuo Liu (ORCID: https://orcid.org/0009-0009-5412-458X)
Institutions
- Nanjing University of Chinese Medicine (CN)
- Shandong University (CN)
- Zhengzhou University (CN)
- Shenzhen Bay Laboratory (CN)
- Second Hospital of Shandong University (CN)
- Nanjing Drum Tower Hospital (CN)
- Henan Provincial People's Hospital (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Qilu Hospital of Shandong University (CN)
- First Affiliated Hospital Zhejiang University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-05-14
- DOI
- https://doi.org/10.1002/advs.202500566
- Citations
- 5
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 7.59
Funders
- Shandong University
- National Natural Science Foundation of China
- National Key Research and Development Program of China