<p>G protein subunit beta 2 (GNB2) is a potential biomarker identified recently in human cancers. However, the specific role and its underlying mechanism in breast cancer (BRCA) remain unclear. Expression levels of GNB2 were examined in human BRCA tissues and cells by real-time quantitative PCR (qPCR), immunohistochemistry (IHC) and Western blot. Biological functions of GNB2 were determined by a series of in vitro experiments (CCK-8, colony formation assay, Transwell and wound healing) and in vivo ones (subcutaneous transplantation tumor and pulmonary metastasis model). Mechanism of GNB2 in BRCA was explored by co-immunoprecipitation (Co-IP), qPCR, Western blot, flow cytometry and some rescue experiments. Increased expression of GNB2 was found in BRCA, which indicated poorer clinical prognosis of the patients. The over-expression of GNB2 increased proliferation, migration of BRCA cells, while it decreased the intracellular contents of reactive oxygen species (ROS), Fe²⁺ and malondialdehyde (MDA). In addition, GNB2 over-expression increased the expression of heat-shock-protein family A(HSP70) member 5 (HSPA5) and the expression of glutathione peroxidase 4 (GPX4), which inhibited the cell death induced from Erastin. After knockdown of GNB2, all the above indicators were significantly reversed. Restored expression of HSPA5 in BRCA cells with GNB2 knockdown rescued the effects. Therefore, the current study verifies GNB2 as an important driver in BRCA progression by up-regulating HSPA5/GPX4 and inhibiting ferroptosis, which highlights its potential role in the clinical diagnosis and treatment of BRCA.</p>