Objective To investigate whether sorafenib can inhibit the growth of human undifferentiated thyroid cancer cell line 8305c by inducing ferroptosis through the Nrf2-xCT/GPX4 axis.

Methods The 8305c cells were cultured in vitro, and treated with Sora (5, 10, 15, 20, 25, 30, 35, 40 µmol/L) for 24 hours. The cell viability was detected by MTT assay. Cells were treated with Sora (5, 15 and 30 μmol/L) for 24 hours, and the intracellular Lipid ROS level was detected by C11-BODIPY (581/591) probe. The antioxidant levels of cells were detected by SOD, T-AOC and NADPH kits. The levels of lipid peroxidation in cells were detected by MDA, TG and NEFA kits. The intracellular lipid droplet levels were observed by oil red O staining. The expression of TFR, Nrf2, xCT and GPX4 proteins was detected by Western blotting.

Results Sora inhibited the proliferation of 8305c cells in a dose-and time-dependent manner (P ＜ 0.01). Compared with the DMSO group, the levels of antioxidants SOD, T-AOC and NADPH in the Sora group decreased (P ＜ 0.01), the levels of Lipid peroxides MAD and Lipid ROS increased (P ＜ 0.01), the levels of fatty acid metabolism indicators TG and NEFA decreased (P ＜ 0.01), intracellular lipid droplets decreased, the protein expressions of Nrf2, xCT and GPX4 significantly decreased, while the protein expression level of TFR increased (P ＜ 0.01). Moreover, compared with the Sora group, the ferroptosis inhibitor Fer-1 could reverse the above protein changes (P ＜ 0.01).

Conclusions Sorafenib induces ferroptosis of human ATC cells 8305c through the Nrf2-xCT /GPX4 axis, thereby inhibiting their growth.