TRIP6/c-Fos regulating GPX4 modulates gastric cancer growth by inhibiting ferroptosis

Background: Gastric cancer (GC) is a digestive system tumor with the highest incidence in China. In recent years, the role of ferroptosis in tumor occurrence and development has received more and more attention. In this study, we sought to identify the genes related to ferroptosis in GC and explain the mechanism of these related genes. Methods: The Cancer Genome Atlas (TCGA) database was analyzed using bioinformatics technology to identify the gene closely related to ferroptosis [i.e., thyroid hormone receptor interacting protein 6 (TRIP6)]. We then constructed the knockdown and overexpression of TRIP6 cell lines to verify the effects of TRIP6 on cell proliferation and ferroptosis using quantitative polymerase chain reaction (qPCR), western blot, co-immunoprecipitation (CO-IP), flow analysis, dual-luciferase report, and other technologies. We also validated the results by ferroptosis inducers and inhibitors. Results: The bioinformatics analysis showed that ferroptosis is closely related to TRIP6. TRIP6 is highly expressed in GC cells and tissues and is associated with a poor prognosis. The knockdown or overexpression of TRIP6 affects cell proliferation and ferroptosis, which we verified via recovery experiments with ferroptosis activators and inhibitors. TRIP6 also affected the expression of glutathione (GSH) peroxidase 4 (GPX4). The CO-IP and silver staining experiments verified that TRIP6 can bind to the transcription factor c-Fos and stabilize its expression. The dual-luciferase experiment confirmed that the transcription factor c-Fos regulated the expression of GPX4. Conclusions: TRIP6, which is highly expressed in GC, binds to and stabilizes the expression of c-Fos, which acts as a transcription factor to regulate the expression of GPX4 and thereby inhibit cell ferroptosis.