IFNγ enhances ferroptosis by increasing JAK-STAT pathway activation to suppress SLCA711 expression in adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is a rare type of tumor with a poor prognosis. Ferroptosis is a relatively novel form of programmed cell death driven by iron-dependent lipid peroxidation accumulation. Recent evidence suggests that IFN gamma facilitates erastin-induced ferroptosis, which contributed to anticancer therapy in various types of cancer. However, it has remained elusive whether the regulation of IFN gamma on ferroptosis has a positive role in the treatment of ACC. Thus, the aim of the present study was to explore the effects of IFN gamma on erastin-induced ferroptosis in the ACC cell line NCI-H295R and investigate the underlying mechanisms. Cell viability was assessed using a Cell Counting Kit-8 assay, an ethynyldioxyuridine proliferation assay and Live/Dead staining. The levels of iron, reactive oxygen species, lipid peroxidation and mitochondrial damage were also assessed. Western blot and reverse transcription-quantitative PCR analyses were used to determine the underlying molecular mechanisms involved in the erastin-induced ferroptosis of NCI-H295R cells. The results suggested that IFN gamma promoted erastin-induced ferroptotic cell death. Furthermore, IFN gamma enhanced erastin-induced ferroptosis, as evidenced by the accumulation of iron, as well as the increase in lipid peroxidation and promotion of mitochondrial damage. Further analysis suggested that IFN gamma enhanced ferroptosis by suppressing the expression of solute carrier family 7 member 11, an important negative regulator of ferroptosis, and this was achieved via activation of the JAK/STAT pathway in NCI-H295R cells. The present study provided experimental evidence on the activity and mechanism of ferroptosis enhanced by IFN gamma in ACC and may give critical insight into the immunotherapeutic management of ACC.

Automated summary

IFN gamma enhances erastin-induced ferroptosis in adrenocortical carcinoma (ACC) cells by suppressing the expression of a negative regulator of ferroptosis and activating the JAK/STAT pathway, leading to increased iron accumulation, lipid peroxidation, and mitochondrial damage.