Tetrandrine citrate suppresses lung adenocarcinoma growth via SLC7A11/GPX4-mediated ferroptosis

Ferroptosis is a mode of programmed cell death that plays a crucial role in tumor biology processes. Although tetrandrine citrate (TetC) has been demonstrated to exert anti-tumor effects, it is still unclear whether TetC inhibits lung adenocarcinoma (LUAD) progression by inducing ferroptosis. The study showcased the inhibitory effect of TetC on the viability and progression of tumor cells, including intracellular iron overload, accumulation of reactive oxygen species (ROS), over-expression of malondial-dehyde (MDA), and depletion of glutathione (GSH). Notably, TetC-induced cell death was clearly reversed by three different ferroptosis-related inhibitors. TetC also induced changes in the mitochondrial morphology of LUAD cells, similar to those observed in typical ferroptosis. Further analysis through Western blot (WB) and Immunofluorescence (IF) assays identified that TetC inhibited the expression and fluorescence intensity of both solute carrier family 7 (SLC7A11) and glutathione peroxidase-4 (GPX4). More importantly, over-expression of SLC7A11 could rescue the TetC-induced ferroptosis. Finally, in our vivo experiment, we discovered that TetC significantly slowed the growth rate of subcutaneous transplanted A549 cells, ultimately proving to be biosafe. In conclusion, our study first identified the mechanism by which TetC-induced ferroptosis in LUAD via SLC7A11/GPX4 signaling.