Downregulation of SLC7A11 by Bis(4‐Hydroxy‐3,5‐Dimethylphenyl) Sulfone Induces Ferroptosis in Hepatocellular Carcinoma Cell

ABSTRACT The progression of tumors has been demonstrated to have a strong correlation with ferroptosis. Bis(4‐hydroxy‐3,5‐dimethylphenyl) sulfone (TMBPS) has been shown to effectively inhibit the proliferation of hepatocellular carcinoma (HCC), but its underlying mechanism is not clear. In this study, ferrostatin‐1 (Fer‐1) was employed to explore whether the death of HCC cells caused by TMBPS is related to ferroptosis. The intracellular lipid peroxides, Fe 2+ , malondialdehyde (MDA), GSH/GSSG, mitochondrial morphology, and potential of HCC cells were detected after TMBPS treatment. The target of TMBPS was predicted by the molecular docking approach and verified via quantitative real‐time polymerase chain reaction (qRT‐PCR), western blot, and cellular heat transfer assay (CETSA). Our results revealed that Fer‐1 effectively reversed the cell death induced by TMBPS in HCC cells. Treatment with TMBPS induced typical ferroptosis features, including increased levels of intracellular lipid peroxides, Fe 2+ , and MDA, along with a decreased GSSH/GSH ratio and mitochondrial potential. These effects were reversed by overexpressing SLC7A11. These findings suggest that the cell death triggered by TMBPS in HCC cells is linked to ferroptosis, potentially mediated through the inhibition of SLC7A11 expression.