Redox Biology (Feb 2024)
Excessive SOX8 reprograms energy and iron metabolism to prime hepatocellular carcinoma for ferroptosis
- Xue Yang,
- Chun Gu,
- Jingshu Cai,
- Feiyang Li,
- Xing He,
- Lunan Luo,
- Wengan Xiao,
- Boyan Hu,
- Jing Hu,
- Hao Qian,
- Shangqing Ren,
- Lin Zhang,
- Xianjun Zhu,
- Lu Yang,
- Jing Yang,
- Zhenglin Yang,
- Yi Zheng,
- Xiang Huang,
- Ziyan Wang
Affiliations
- Xue Yang
- The Sichuan Provincial Key Laboratory for Human Disease Gene, Study Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China; Laboratory of Ageing Research, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China
- Chun Gu
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China; Department of Hepatobiliary & Pancreatic Center, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China; Department of Hepatobiliary & Pancreatic Center, Chinese Academy of Medical Sciences and Sichuan Translational Medicine Research Hospital, Chengdu, Sichuan, 610072, China
- Jingshu Cai
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China; The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Feiyang Li
- Laboratory of Ageing Research, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China
- Xing He
- The Sichuan Provincial Key Laboratory for Human Disease Gene, Study Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China; Laboratory of Ageing Research, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China
- Lunan Luo
- Laboratory of Ageing Research, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China
- Wengan Xiao
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China
- Boyan Hu
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China
- Jing Hu
- The Sichuan Provincial Key Laboratory for Human Disease Gene, Study Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China
- Hao Qian
- The Sichuan Provincial Key Laboratory for Human Disease Gene, Study Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China
- Shangqing Ren
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China; Robotic Minimally Invasive Surgery Center, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, 610072, China
- Lin Zhang
- The Sichuan Provincial Key Laboratory for Human Disease Gene, Study Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China; Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, 610072, China
- Xianjun Zhu
- The Sichuan Provincial Key Laboratory for Human Disease Gene, Study Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China; Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, 610072, China
- Lu Yang
- Laboratory of Ageing Research, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China
- Jing Yang
- Laboratory of Ageing Research, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China; Corresponding authors. Laboratory of Ageing Research, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China.
- Zhenglin Yang
- The Sichuan Provincial Key Laboratory for Human Disease Gene, Study Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China; Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, 610072, China; Corresponding author. The Sichuan Provincial Key Laboratory for Human Disease Gene, Study Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China.
- Yi Zheng
- Laboratory of Ageing Research, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China; Corresponding authors. Laboratory of Ageing Research, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China.
- Xiang Huang
- The Sichuan Provincial Key Laboratory for Human Disease Gene, Study Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China; Department of Urology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China; Corresponding author. The Sichuan Provincial Key Laboratory for Human Disease Gene, Study Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China.
- Ziyan Wang
- The Sichuan Provincial Key Laboratory for Human Disease Gene, Study Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China; Laboratory of Ageing Research, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China; Corresponding authors. The Sichuan Provincial Key Laboratory for Human Disease Gene, Study Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China.
- Journal volume & issue
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Vol. 69
p. 103002
Abstract
Lipid peroxidation and redox imbalance are hallmarks of ferroptosis, an iron-dependent form of cell death. Growing evidence suggests that dysregulation in glycolipid metabolism and iron homeostasis substantially contribute to the development of hepatocellular carcinoma (HCC). However, there is still a lack of comprehensive understanding regarding the specific transcription factors that are capable of coordinating glycolipid and redox homeostasis to initiate the onset of ferroptosis. We discovered that overexpression of SOX8 leads to impaired mitochondria integrate, increased oxidative stress, and enhanced lipid peroxidation. These effects can be attributed to the inhibitory impact of SOX8 on de novo lipogenesis, glycolysis, the tricarboxylic acid cycle (TCA), and the pentose phosphate pathway (PPP). Additionally, upregulation of SOX8 results in reduced synthesis of NADPH, disturbance of redox homeostasis, disruption of mitochondrial structure, and impairment of the electron transport chain. Furthermore, the overexpression of SOX8 enhances the process of ferroptosis by upregulating the expression of genes associated with ferroptosis and elevating intracellular levels of ferrous ion. Importantly, the overexpressing of SOX8 has been observed to inhibit the proliferation of HCC in immunodeficient animal models. In conclusion, the findings suggest that SOX8 has the ability to alter glycolipid and iron metabolism of HCC cells, hence triggering the process of ferroptosis. The results of our study present a novel strategy for targeting ferroptosis in the therapy of HCC.
