IFNγ-mediated repression of system xc- drives vulnerability to induced ferroptosis in hepatocellular carcinoma cells

IFN gamma released from CD8(+) T cells or natural killer cells plays a crucial role in antitumor host immunity. Several studies have found that IFN gamma is involved in regulating tumor cell proliferation and apoptosis. However, few studies have examined its role in cell ferroptosis. Here, we found that IFN gamma treatment enhanced glutathione depletion, promoted cell cycle arrested in G0/G1 phase, increased lipid peroxidation, and sensitized cells to ferroptosis activators. Additionally, IFN gamma down-regulated the mRNA and protein levels of SLC3A2 and SLC7A11, two subunits of the glutamate-cystine antiporter system xc(-) via activating the JAK/STAT pathway in hepatocellular carcinoma (HCC) cell lines. Furthermore, IFN gamma increased reactive oxygen species levels and decreased mitochondiral membrane potential in Bel7402 and HepG2 cells. These changes were accompanied by decreased system xc(-) activity. Cancer cells exposed to TGF beta 1 for 48 h showed sensitization to IFN gamma + erastin-induced ferroptosis, with decreased system xc(-) expression. In conclusion, IFN gamma repressed system xc(-) activation via activating JAK/STAT signaling. Additionally, enhanced lipid peroxidation was associated with altered mitochondrial function in HCC cells. Our findings identified a role for IFN gamma in sensitizing HCC cells to ferroptosis, which provided new insights for applying IFN gamma as a cancer treatment.