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bioRxiv · 10.1101/2020.12.14.422655

GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis

Wang, Q.·Cheng, B.·Xue, Q.·Gao, Q.·Huang, A.·Wang, K.·Tang, N.
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Abstract

Increasing evidence supports that ferroptosis plays an important role in tumor growth inhibition. Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, has been shown to induce ferroptosis in hepatocellular carcinoma (HCC). However, some hepatoma cell lines are less sensitive to sorafenib-induced ferroptotic cell death. Glutathione S-transferase zeta 1 (GSTZ1), an enzyme in the catabolism of phenylalanine, has been found to negatively regulate the master regulator of cellular redox homeostasis nuclear factor erythroid 2-related factor 2 (NRF2). This study aimed to investigate the role of GSTZ1 in sorafenib-induced ferroptosis in HCC cell lines and determine the involved molecular mechanisms. Mechanistically, GSTZ1 depletion enhanced the activation of the NRF2 pathway and increased the glutathione peroxidase 4 (GPX4) level, thereby suppressing sorafenib-induced ferroptosis. The combination of sorafenib and RSL3, a GPX4 inhibitor, significantly inhibited GSTZ1 deficient cell viability and promoted ferroptosis, accompanied with ectopic increases of iron and lipid peroxides. An in vivo experiment showed that the combination of sorafenib and RSL3 had a synergic therapeutic effect on HCC progression in Gstz1-/- mice. In conclusion, GSTZ1 was significantly downregulated in sorafenib resistant hepatoma cells. GSTZ1 enhanced sorafenib-induced ferroptosis by inhibiting the NRF2/GPX4 axis in HCC cells. GSTZ1 deficiency was resistant to sorafenib-induced ferroptosis and is, therefore, a potential therapeutic approach for treating HCC by synergizing sorafenib and RSL3 to induce ferroptosis.

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Wang, Q., Cheng, B., Xue, Q., Gao, Q., Huang, A., Wang, K., Tang, N.. 2020-12-14. GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis. https://doi.org/10.1101/2020.12.14.422655

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