SOX8 Promotes Ferroptosis By Regulating Lipid And Glucose Metabolism In Hepatocellular Carcinoma

The incidence and mortality of hepatocellular carcinoma(HCC)are extremely high worldwide.The current treatment for HCC is mainly surgery,but patients with HCC have a poor prognosis and the 10-year survival rate is only 7.2%.The factors that promote HCC are complex.More than 90% of HCC originate from chronic liver disease,and the incidence of HCC caused by non-viral non-alcoholic hepatitis is rapidly increasing.Previous Studies have confirmed that remodeling of glycolipid metabolism plays an important role in HCC progression,and the intervention of glycolipid metabolism pathways would inhibit the growth of HCC cells.Lipid peroxidation and iron-dependent ferroptosis is becoming a new target in cancer treatment.However,how to induce ferroptosis by reprogramming glucose and lipid metabolism of tumor cells needs to be further explored.The transcription factor SOX8 is associated with multiple cancer development,but the regulatory mechanism of SOX8 has not been deeply studied.This project aims to explore the biological role and molecular mechanism of SOX8 in regulating lipid metabolism and ferroptosis in cancer cells.We analyzed the ferroptotic signal,lipid synthesis and energy metabolism by overexpression of SOX8 in HCC and prostate cancer cells.We found that overexpression of SOX8 widely inhibited the expression of de novo synthesis-related enzymes of fatty acids and the expression of enzymes in the cellular pentose phosphate pathway,reduced NADPH synthesis,broken the balance of redox system,destroyed the structure and function of mitochondria,damages the electron transport chain to cause the accumulation of ROS and lipid peroxides.Overexpression of SOX8 increased the expression of ferroptosis-related genes(transferrin,transferrin receptor protein,15-LOX et al)and the intracellular ferrous ion levels,which finally promoted ferroptosis.Moreover,SOX8 inhibited the HCC growth in immunodeficient mice.The study elucidates the molecular mechanism of SOX8 in regulating ferroptosis by participating in glycolipid metabolism of cancer cells.SOX8 could not only inhibit the expression of fatty acid de novo synthase,but also represses glycolysis,TCA cycle and pentose phosphate pathway.SOX8 remodels the glycolipid and iron metabolism of cancer cells to break the redox balance.This study provides a new strategy for targeting ferroptosis in cancer therapy.