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Gallium Triggers Ferroptosis through a Synergistic Mechanism |
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| Authors: | Xin-Xin Peng Hang Zhang Ruijing Zhang Ze-Hao Li Zi-Shu Yang Jing Zhang Song Gao Jun-Long Zhang |
| Institution: | 1. Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871 P. R. China;2. Spin-X Institute, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, 510641 P. R. China;3. Center of Materials Science and Optoelectronics Engineering, College of Materials Science and Opto-Electronic Technology, University of Chinese Academy of Sciences, Beijing, 100049 P. R. China;4. Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871 P. R. China
Spin-X Institute, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, 510641 P. R. China Chemistry and Chemical Engineering Guangdong Laboratory, Shantou, 515031 P. R. China School of Chemistry, Sun Yat-sen University, Guangzhou, 510275 P. R. China |
| Abstract: | The gallium ion (Ga3+) has long been believed to disrupt ferric homeostasis in the body by competing with iron cofactors in metalloproteins, ultimately leading to cell death. This study revealed that through an indirect pathway, gallium can trigger ferroptosis, a type of non-apoptotic cell death regulated by iron. This is exemplified by the gallium complex of the salen ligand ( Ga-1 ); we found that Ga-1 acts as an effective anion transporter that can affect the pH gradient and change membrane permeability, leading to mitochondrial dysfunction and the release of ferrous iron from the electron transfer chain (ETC). In addition, Ga-1 also targeted protein disulfide isomerases (PDIs) located in the endoplasmic reticulum (ER) membrane, preventing the repair of the antioxidant glutathione (GSH) system and thus enforcing ferroptosis. Finally, a combination treatment of Ga-1 and dietary polyunsaturated fatty acids (PUFAs), which enhances lipid peroxidation during ferroptosis, showed a synergistic therapeutic effect both in vitro and in vivo. This study provided us with a strategy to synergistically induce Ferroptosis in tumor cells, thereby enhancing the anti-neoplastic effect. |
| Keywords: | Anticancer Ferroptosis Gallium Metallodrug |