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  3. Dipyridamole Acts as Clinical Ferroptosis Inhibitor to Prevent from Tissue Injury

Dipyridamole Acts as Clinical Ferroptosis Inhibitor to Prevent from Tissue Injury

  • Adv Sci (Weinh). 2025 Jun;12(23):e2500566. doi: 10.1002/advs.202500566.
Xiao Zhuang 1,  Shuang Shi 2,  Shuo Liu 1 3,  Yaqiong Jiao 4,  Bin Huang 5,  Yinghong Yang 1,  Li Yang 6,  Xinquan Yang 7,  Hui Wang 5,  Chunhui Liang 1,  Dandan Song 1,  Huaxiang Yu 8,  Dan Zou 8,  Qi Sun 9,  Shu Yang 10,  Chengqian Yin 5,  Jian Li 9,  Yiming Liu 11,  Junxia Min 7,  Fudi Wang 12,  Yong Nian 10,  Lutao Du 13 14,  Bo Chu 1
Affiliations

Affiliations

  • 1 Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
  • 2 Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, 250012, China.
  • 3 Department of Geriatric Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
  • 4 Department of General Practice, Qilu Hospital of Shandong University, Jinan, 250012, China.
  • 5 Institute for Cancer Research, Shenzhen Bay Laboratory, Shenzhen, 518107, China.
  • 6 Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, 450003, China.
  • 7 The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 8 Department of Emergency Medicine and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China.
  • 9 Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, 250012, China.
  • 10 College of Pharmacy, Nanjing drum tower hospital, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 11 Department of Neurology, Qilu Hospital of Shandong University, Jinan, 250012, China.
  • 12 The First Affiliated Hospital, The Second Affiliated Hospital, Institute of Translational Medicine, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 13 Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, 250012, China.
  • 14 Shandong Provincial Key Laboratory of Innovation Technology in Laboratory Medicine, Jinan, 250012, China.
PMID: 40365742 DOI: 10.1002/advs.202500566
Abstract

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.

Keywords

SLC7A11; dipyridamole; ferroptosis; tissue injury.

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