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

Abstract

IFNγ released from CD8+ T cells or natural killer cells plays a crucial role in antitumor host immunity. Several studies have found that IFNγ is involved in regulating tumor cell proliferation and apoptosis. However, few studies have examined its role in cell ferroptosis. Here, we found that IFNγ treatment enhanced glutathione depletion, promoted cell cycle arrested in G0/G1 phase, increased lipid peroxidation, and sensitized cells to ferroptosis activators. Additionally, IFNγ 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, IFNγ 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 TGFβ1 for 48 h showed sensitization to IFNγ + erastin‐induced ferroptosis, with decreased system xc− expression. In conclusion, IFNγ 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 IFNγ in sensitizing HCC cells to ferroptosis, which provided new insights for applying IFNγ as a cancer treatment.

Ferroptosis: A Critical Moderator in the Life Cycle of Immune Cells

“…A study investigated the effect of IFNγ on hepatocellular carcinoma (HCC) found that IFNγ enhanced the consumption of GSH, increased lipid peroxidation, and increased the sensitivity of HCC to ferroptosis. At the same time, IFNγ induces ferroptosis in HCC by activating JAK/STAT signal transduction and inhibiting system ( 76 ). But in TME, NK cells dysfunction occurs.…”

The multifaceted role of ferroptosis in liver disease

“…Recently, IFNγ was used to sensitize HCC cells to ferroptosis by suppressing system x c - via activation of the JAK/STAT signaling pathway, thus providing new insights into the feasibility of using IFNγ to induce ferroptosis in treating HCC [ 100 ]. In addition, the progression of HCC was recently linked to the circ0097009/miR-1261/SLC7A11 axis [ 101 ].…”

A Risk Model Based on Sorafenib-Response Target Genes Predicts the Prognosis of Patients with HCC

“…e PPAR signaling pathway, antigen processing and presentation, and ferroptosis are associated with cancer growth and metastasis [22][23][24][25][26][27]. For example, the overexpression of the lncRNA TINCR inhibits colorectal cancer (CRC) cell proliferation and promotes apoptosis.…”