Fra-1 affects chemotherapy sensitivity by inhibiting ferroptosis in gastric cancer cells

Aim: Gastric cancer (GC) is one of the common malignant tumors, and most patients with advanced GC often develop chemotherapy resistance, resulting in poor chemotherapy efficacy. Therefore, it is crucial to clarify the specific mechanisms of their chemotherapy resistance. Methods: In this study, we analyzed the correlation between fos-related antigen-1 (Fra-1) and chemotherapy resistance in GC using bioinformatics, cell counting kit-8 (CCK8), and 5-ethynyl-2’-deoxyuridine (EDU) combined with flow cytometry; furthermore, we used energy metabolomics sequencing, combined with ChIP-qPCR technology, to elucidate the specific role of Fra-1 in chemotherapy resistance of GC cells and its related mechanisms. Results: We found that high Fra-1 expression was closely related to chemotherapeutic drugs in GC cells, as demonstrated by bioinformatics analysis combined with EDU and CCK8 experiments. Energy metabolomics combined with in vitro cellular experimental analysis revealed that the pentose phosphate pathway (PPP) was activated in GC cells with high Fra-1 expression, along with an increase in the synthesis of metabolites such as nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), a decrease in the level of reactive oxygen species (ROS), and the inhibition of their ferroptosis. In addition, ChIP-qPCR experiments confirmed that Fra-1 binds to the promoter of glucose-6-phosphate dehydrogenase (G6PD), a key rate-limiting enzyme of the PPP, and transcriptionally regulates its expression, which in turn activates the PPP and promotes chemotherapy resistance in GC cells. Conclusion: Our research findings suggest that Fra-1 activates the PPP by upregulating G6PD transcriptional activity and inhibiting its ubiquitination level, inhibiting ferroptosis in GC cells and inducing chemoresistance. This provides an experimental basis for screening potential molecular targets for chemotherapy resistance in GC patients.