Yunpeng Wei1, Huanhuan Lv2, Atik Badshah Shaikh1, Wei Han1, Hongjie Hou3, Zhihao Zhang3, Shenghang Wang3, Peng Shang4. 1. Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen 518057, China. 2. Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen 518057, China; School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, China; Key Laboratory for Space Biosciences and Biotechnology, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, China. 3. School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, China; Key Laboratory for Space Biosciences and Biotechnology, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, China. 4. Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen 518057, China; Key Laboratory for Space Biosciences and Biotechnology, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, China. Electronic address: shangpeng@nwpu.edu.cn.
Abstract
BACKGROUND: Cancer is one of the major threats to human health and current cancer therapies have been unsuccessful in eradicating it. Ferroptosis is characterized by iron-dependence and lipid hydroperoxides accumulation, and its primary mechanism involves the suppression of system Xc--GSH (glutathione)-GPX4 (glutathione peroxidase 4) axis. Co-incidentally, cancer cells are also metabolically characterized by iron addiction and ROS tolerance, which makes them vulnerable to ferroptosis. This may provide a new tactic for cancer therapy. SCOPE OF REVIEW: The general features and mechanisms of ferroptosis, and the basis that makes cancer cells vulnerable to ferroptosis are described. Further, we emphatically discussed that disrupting GSH may not be ideal for triggering ferroptosis of cancer cells in vivo, but directly inhibiting GPX4 and its compensatory members could be more effective. Finally, the various approaches to directly inhibit GPX4 without disturbing GSH were described. MAJOR CONCLUSIONS: Targeting system Xc- or GSH may not effectively trigger cancer cells' ferroptosis in vivo the existence of other compensatory pathways. However, directly targeting GPX4 and its compensatory members without disrupting GSH may be more effective to induce ferroptosis in cancer cells in vivo, as GPX4 is essential in preventing ferroptosis. GENERAL SIGNIFICANCE: Cancer is a severe threat to human health. Ferroptosis-based cancer therapy strategies are promising, but how to effectively induce ferroptosis in cancer cells in vivo is still a question without clear answers. Thus, the viewpoints raised in this review may provide some references and different perspectives for researchers working on ferroptosis-based cancer therapy.
BACKGROUND:Cancer is one of the major threats to human health and current cancer therapies have been unsuccessful in eradicating it. Ferroptosis is characterized by iron-dependence and lipid hydroperoxides accumulation, and its primary mechanism involves the suppression of system Xc--GSH (glutathione)-GPX4 (glutathione peroxidase 4) axis. Co-incidentally, cancer cells are also metabolically characterized by iron addiction and ROS tolerance, which makes them vulnerable to ferroptosis. This may provide a new tactic for cancer therapy. SCOPE OF REVIEW: The general features and mechanisms of ferroptosis, and the basis that makes cancer cells vulnerable to ferroptosis are described. Further, we emphatically discussed that disrupting GSH may not be ideal for triggering ferroptosis of cancer cells in vivo, but directly inhibiting GPX4 and its compensatory members could be more effective. Finally, the various approaches to directly inhibit GPX4 without disturbing GSH were described. MAJOR CONCLUSIONS: Targeting system Xc- or GSH may not effectively trigger cancer cells' ferroptosis in vivo the existence of other compensatory pathways. However, directly targeting GPX4 and its compensatory members without disrupting GSH may be more effective to induce ferroptosis in cancer cells in vivo, as GPX4 is essential in preventing ferroptosis. GENERAL SIGNIFICANCE: Cancer is a severe threat to human health. Ferroptosis-based cancer therapy strategies are promising, but how to effectively induce ferroptosis in cancer cells in vivo is still a question without clear answers. Thus, the viewpoints raised in this review may provide some references and different perspectives for researchers working on ferroptosis-based cancer therapy.