Glutathione peroxidase 4 (GPx4; also known as phospholipid hydroperoxide glutathione peroxidase) inhibits cell death, including apoptosis and ferroptosis, by reducing lipid peroxidation. In addition, western blot assays showed that GPx4 protein levels were elevated in hepatocellular carcinoma (HCC) cells following triptolide (TPL) treatment. Therefore, it was hypothesized that HCC cells might develop partial resistance to TPL‑induced cytotoxicity through upregulation of the GPx4 protein. To enhance anti‑proliferative efficacy, the present study co‑treated HCC cells with a combination of TPL and RAS‑selective lethal 3 (RSL3), a well‑characterized GPx4 activity inhibitor. Subsequent experimental data produced from Cell Counting Kit‑8 and flow cytometric analyses demonstrated that co‑administration of TPL and RSL3 promoted HCC cell apoptosis, elevated intracellular reactive oxygen species levels and induced ferroptosis. These collective findings suggested that co‑treatment with TPL and RSL3 may induce both apoptotic and ferroptotic pathways in HCC cells.