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Significance The cancer-dependent metabolic rewiring is mainly associated with the synthesis of building blocks that are needed to fulfill the proliferating cell metabolic requirements. However, the proliferation-independent instructive role of metabolic enzymes in tumor plasticity is still unclear. Here, we introduce glutathione peroxidase 8 (GPX8) as a metabolic enzyme that regulates cancer aggressiveness. We found that lack of GPX8 suppresses the aggressive phenotype and stemness features of the tumor cells. Mechanistically, these cells express a nonfunctional IL-6 receptor, which fails to interact with IL-6. This impaired binding hinders the activation of the downstream JAK/STAT3 signaling pathway, thereby inhibiting cancer cells transition to aggressive phenotypes. Thus, we present this GPX8/IL-6/STAT3 axis as a prototype of metabolic enzymes regulating cancer aggressiveness-associated signaling pathways.

The glutathione peroxidase 8 (GPX8)/IL-6/STAT3 axis is essential in maintaining an aggressive breast cancer phenotype