Excessive SOX8 reprograms energy and iron metabolism to prime hepatocellular carcinoma for ferroptosis

作者全名:"Yang, Xue; Gu, Chun; Cai, Jingshu; Li, Feiyang; He, Xing; Luo, Lunan; Xiao, Wengan; Hu, Boyan; Hu, Jing; Qian, Hao; Ren, Shangqing; Zhang, Lin; Zhu, Xianjun; Yang, Lu; Yang, Jing; Yang, Zhenglin; Zheng, Yi; Huang, Xiang; Wang, Ziyan"

作者地址:"[Yang, Xue; He, Xing; Hu, Jing; Qian, Hao; Zhang, Lin; Zhu, Xianjun; Yang, Zhenglin; Huang, Xiang; Wang, Ziyan] Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Dept Lab Med, Study Ctr Med Genet,Sichuan Prov Key Lab Human Dis, Chengdu 610072, Sichuan, Peoples R China; [Yang, Xue; Li, Feiyang; He, Xing; Luo, Lunan; Yang, Lu; Yang, Jing; Zheng, Yi; Wang, Ziyan] Univ Elect Sci & Technol China, Sch Med, Lab Ageing Res, Chengdu 610054, Sichuan, Peoples R China; [Yang, Xue; Gu, Chun; Cai, Jingshu; Li, Feiyang; He, Xing; Luo, Lunan; Xiao, Wengan; Hu, Boyan; Hu, Jing; Qian, Hao; Ren, Shangqing; Zhang, Lin; Zhu, Xianjun; Yang, Lu; Yang, Jing; Yang, Zhenglin; Zheng, Yi; Huang, Xiang; Wang, Ziyan] Univ Elect Sci & Technol China, Sch Med, Chengdu 610054, Sichuan, Peoples R China; [Gu, Chun] Univ Elect Sci & Technol China, Sch Med, Sichuan Prov Peoples Hosp, Dept Hepatobiliary & Pancreat Ctr, Chengdu 610072, Sichuan, Peoples R China; [Gu, Chun] Univ Elect Sci & Technol China, Sch Med, Sichuan Prov Peoples Hosp, Pancreat Ctr, Chengdu 610072, Sichuan, Peoples R China; [Gu, Chun] Chinese Acad Med Sci, Dept Hepatobiliary, Chengdu 610072, Sichuan, Peoples R China; [Gu, Chun] Chinese Acad Med Sci, Pancreat Ctr, Chengdu 610072, Sichuan, Peoples R China; [Gu, Chun] Sichuan Translat Med Res Hosp, Chengdu 610072, Sichuan, Peoples R China; [Cai, Jingshu] Chongqing Med Univ, Affiliated Hosp 1, Chongqing Key Lab Translat Med Major Metab Dis, Chongqing 400016, Peoples R China; [Ren, Shangqing] Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Robot Minimally Invas Surg Ctr, Chengdu 610072, Peoples R China; [Zhang, Lin; Zhu, Xianjun; Yang, Zhenglin] Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Res Unit Blindness Prevent Chinese Acad Med Sci 20, Chengdu 610072, Sichuan, Peoples R China; [Huang, Xiang] Univ Elect Sci & Technol China, Sch Med, Sichuan Prov Peoples Hosp, Dept Urol, Chengdu 610072, Sichuan, Peoples R China"

通信作者:"Yang, ZL; Huang, X; Wang, ZY (通讯作者),Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Dept Lab Med, Study Ctr Med Genet,Sichuan Prov Key Lab Human Dis, Chengdu 610072, Sichuan, Peoples R China.; Yang, J; Zheng, Y; Wang, ZY (通讯作者),Univ Elect Sci & Technol China, Sch Med, Lab Ageing Res, Chengdu 610054, Sichuan, Peoples R China."

来源:REDOX BIOLOGY

ESI学科分类:BIOLOGY & BIOCHEMISTRY

WOS号:WOS:001146505600001

JCR分区:Q1

影响因子:10.7

年份:2024

卷号:69

期号: 

开始页: 

结束页: 

文献类型:Article

关键词:China; SOX8; Glycolipid metabolism; Ferroptosis; Iron metabolism; HCC

摘要:"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 , 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."

基金机构:"Natural Science Foundation of China [81790642, 82121003, 12102086]; Natural Science Foundation of Sichuan Province [2020YFS0420, 2021YFS0404, 2021YFS0369, 2022NSFSC0607, 2022YFS0599, 2021YJ0182, 2019-12M-5-032]; Chinese Academy of Medical Sciences [82271276]; [2021YJ0196]"

基金资助正文:"This study was supported by grants from the Natural Science Foundation of China (81790642, 82121003, 82271276, 12102086) , the Natural Science Foundation of Sichuan Province (2021YJ0196, 2020YFS0420, 2021YFS0404, 2021YFS0369, 2022NSFSC0607, 2022YFS0599, 2021YJ0182) and Chinese Academy of Medical Sciences (2019-12M-5-032) . The authors alone are responsible for the content and writing of the paper."