miR-6126 modulates GRP78 to suppress the Warburg effect and mitochondrial dynamics in triple-negative breast cancer

Cancer cells often exhibit a metabolic shift towards aerobic glycolysis, known as the Warburg effect, leading to excessive energy production that facilitates tumorigenesis, including in breast cancer. Recently, non-coding RNAs, including microRNAs (miRNAs), have been identified as playing crucial roles in various human cancers. However, their roles in regulating metabolic reprogramming in breast cancer remain largely unexplored. Here, we identified the novel miRNA miR-6126, which is highly expressed in TNBC cells by using a miRNA microarray analysis. Overexpression of miR-6126 reduced the growth of TNBC cells and induced apoptosis by targeting GRP78 in vitro and in vivo. In addition, a luciferase reporter assay confirmed that GRP78 is a direct target of miR-6126. Elevated glucose metabolism, indicated by increased levels of LDHA and glucose transporter-1, was observed in TNBC following GRP78 overexpression. Treatment with miR-6126 mimics or GRP78 siRNA not only reduced LDHA and GLUT1 expression but also decreased glucose uptake and lactate release in TNBC cells. Moreover, miR-6126 impaired mitochondrial function by inducing mitochondrial fission through the downregulation of phospho-Drp1 (Ser616) and FIS1. Furthermore, we demonstrated that the expression of miR-6126 is negatively correlated with GRP78 in human tumor tissues. Our findings revealed that miR-6126 is implicated in tumorigenesis via the Warburg effect by targeting GRP78 and restoring mitochondrial function in TNBC.