Yang 2023 Redox Biol

Yang X, Gu C, Cai J, Li F, He X, Luo L, Xiao W, Hu B, Hu J, Qian H, Ren S, Zhang L, Zhu X, Yang L, Yang J, Yang Z, Zheng Y, Huang X, Wang Z (2023) Excessive SOX8 reprograms energy and iron metabolism to prime hepatocellular carcinoma for ferroptosis. https://doi.org/10.1016/j.redox.2023.103002

» Redox Biol [Epub ahead of print]. PMID: 38142583 Open Access

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 (2023) Redox Biol

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. • Keywords: Ferroptosis, Glycolipid metabolism, HCC, Iron metabolism, SOX8 • Bioblast editor: Plangger M

Labels: MiParea: Respiration, Genetic knockout;overexpression 

Stress:Cell death  Organism: Human  Tissue;cell: Liver  Preparation: Intact cells 

Coupling state: LEAK, ROUTINE, ET  Pathway: ROX  HRR: Oxygraph-2k 

2024-01, CN