Ferroptosis is potential to relieve drug resistance in hepatocellular carcinoma (HCC). Glutathione peroxidase 4 (GPX4) is a critical modulator of ferroptosis. This study discussed the mechanism of GPX4-inhibited ferroptosis in sorafenib resistance in HCC. HCG18 in HCC cells was detected. Sorafenib resistant (SR) cell line Huh7-SR cells were treated with sorafenib (0, 2.5, 5, 7.5, 10 μM). After silencing HCG18 in Huh7-SR cells, cell activity, proliferation and apoptosis were detected. The levels of iron, the concentration of MDA, GSH and lipid reactive oxygen species (ROS) were measured to evaluate the ferroptosis. The downstream mechanism of HCG18 was predicted and verified. Huh7-SR cells were infected with lentivirus sh-HCG18 to establish xenograft tumor model. HCG18 was elevated in HCC cells and associated with sorafenib resistance. Silencing HCG18 inhibited cell proliferation, promoted apoptosis, and impaired sorafenib resistance. Ferroptosis was inhibited in Huh7-SR cells, while silencing HCG18 inhibited sorafenib resistance by promoting ferroptosis. GPX4 overexpression averted the promotion of sh-HCG18 on ferroptosis, thereby reducing sorafenib resistance. HCG18 sponged miR-450b-5p to regulate GPX4. Collectively, Silencing HCG18 inhibits GPX4 by binding to miR-450b-5p, promotes GPX4-inhibited ferroptosis, and averts sorafenib resistance in HCC.
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