Background Hepatocellular carcinoma (HCC) is among the most common forms of cancer and is associated with poor patient outcomes. The emergence of therapeutic resistance has hampered the efficacy of targeted treatments employed to treat HCC patients to date. In this study, we conducted a series of CRISPR/Cas9 screens to identify genes associated with synthetic lethality capable of improving HCC patient clinical responses. Methods CRISPR-based loss-of-function genetic screens were used to target 18,053 protein-coding genes in HCC cells to identify chemotherapy-related synthetic lethal genes in these cells. Synergistic effects were analyzed through in vitro and in vivo analyses, while related mechanisms were explored through RNA-seq and metabolomics analyses. Potential inhibitors of identified genetic targets were selected through high-throughput virtual screening. Results The inhibition of phosphoseryl-tRNA kinase (PSTK) was found to increase HCC cell sensitivity to chemotherapeutic treatment. PSTK was associated with the suppression of chemotherapy-induced ferroptosis in HCC cells, and the depletion of PSTK resulted in the inactivation of glutathione peroxidative 4 (GPX4) and the disruption of glutathione (GSH) metabolism owing to the inhibition of selenocysteine and cysteine synthesis, thus enhancing the induction of ferroptosis upon targeted chemotherapeutic treatment. Punicalin, an agent used to treat hepatitis B virus (HBV), was identified as a possible PSTK inhibitor that exhibited synergistic efficacy when applied together with Sorafenib to treat HCC in vitro and in vivo. Conclusions These results highlight a key role for PSTK as a mediator of resistance to targeted therapeutic treatment in HCC cells that functions by suppressing ferroptotic induction. PSTK inhibitors may thus represent ideal candidates for overcoming drug resistance in HCC.

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Utilizing oxidative stress has recently been regarded as a potential strategy for tumor therapy. The NUAK family SNF1like kinase 1 (NUAK1) is a critical component of the antioxidant defense system and is necessary for the survival of tumors. Therefore, NUAK1 is considered an attractive therapeutic target in cancer. However, antioxidant therapy induced elevated ROS levels to activate the Unc-51-like kinase 1 (ULK1) pathway to promote protective autophagy and ULK1-dependent mitophagy. Thus, the combined inhibition of NUAK1 and ULK1 showed a strong synergistic effect in different tumor types. Herein, the potential antitumor activities of a dual NUAK1/ULK1 inhibitor MRT68921 were evaluated in both tumor cell lines and animal models. MRT68921 significantly kills tumor cells by breaking the balance of oxidative stress signals. These results highlight the potential of MRT68921 as an effective agent for tumor therapy.