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

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, suppresses the expression of the master regulator of cellular redox homeostasis nuclear factor erythroid 2-related factor 2 (NRF2). This study aimed to investigate the role and underlying molecular mechanisms of GSTZ1 in sorafenib-induced ferroptosis in HCC. GSTZ1 was significantly downregulated in sorafenib-resistant hepatoma cells. 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 and increased ectopic iron and lipid peroxides. In vivo, the combination of sorafenib and RSL3 had a synergic therapeutic effect on HCC progression in Gstz1−/− mice. In conclusion, this finding demonstrates that GSTZ1 enhanced sorafenib-induced ferroptosis by inhibiting the NRF2/GPX4 axis in HCC cells. Combination therapy of sorafenib and GPX4 inhibitor RSL3 may be a promising strategy in HCC treatment.

Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis

“…Increasing evidence has also shown that NRF2 can improve the resistance of cancer cells to chemotherapeutic drugs [ 7 , 24 ]. In HCC, it's confirmed that NRF2 is upregulated in tumor tissues, and transcriptionally activates the ferroptosis-related genes such as HO-1, FTH1, and NQO1, which is associated with malignancy and a poor prognosis [ 7 , 39 , 40 ]. Therefore, inhibition of Keap1-NRF2-ARE signal system may represent an attractive approach for the reversal of drug resistance.…”

Molecular Targets of Ferroptosis in Hepatocellular Carcinoma

“…Previous studies have shown that a lack of GSTZ1 can lead to the accumulation of the metabolite succinyl lactone, which activates the NRF2 signaling pathway. [103][104][105] Wang et al 106 found that the depletion of GSTZ1 potentiated the NRF2 pathway and elevated the level of GPX4, thus inhibiting sorafenib-induced ferroptosis. Louandre et al 107 found that retinoblastoma mediates ferroptosis and kills HCC cells by participating in the toxic effects of sorafenib on HCC cells.…”

In Vivo and In Vitro Models of Hepatocellular Carcinoma: Current Strategies for Translational Modeling

“…The ability to induce HCC as a late event of CCl 4 induction was used in mice (16% in corn oil, 3x/week/8 weeks) to evaluate the treatment of Sorafenib+ MAPK/ERK pathway inhibitors [ 396 ]. On the other hand, studies also associate the carcinogenic action of DEN with the fibro-cirrhotic capacity of CCl 4 in the chemo [ 397 ] and immunotherapeutic tests [ 398 ]. TAA has also been used in preclinical tests in mice (200 mg/Kg ip or 200 mg/L in drinking water) associated or not with syngeneic and xenographic models, enabling the evaluation of drugs with known or promising potential, chemo or immunotherapy [ 386 , 388 , 399 ].…”

“…Genetic engineering enabled the creation of transgenic animals with structural and metabolic alterations totally directed to the specificity of the questions formulated for the object of study. In the preclinical researches of HCC, these animals can be inserted in different models, directing the results to a specific signaling pathway both in the testing of new drugs [ 386 , 388 , 396 , 397 ] and in new therapies [ 388 , 389 , 390 , 398 ].…”

“…The results not only proved the efficient destruction of CPC3 positive cells but also proved that CPC3 is not present in normal cells and can be an HCC-specific antigen and, therefore, an excellent therapeutic target [ 390 ]. Currently, preclinical studies combine numerous tools such as liver cell lines, syngeneic and xenographic models, chemical induction and transgenic animals [ 386 , 388 , 393 , 396 , 397 , 399 ] in search of treatment alternatives for HCC.…”