PLA2G4F is a metabolic checkpoint in triple-negative breast cancer: Insights from multiple omics analysis and experiments

Metabolic reprogramming is an emerging hallmark and promising therapeutic target in cancer, fueling malignant cells and regulating the tumor microenvironment as a metabolic checkpoint. Triple-negative breast cancer (TNBC), an aggressive subtype with poor prognosis, is marked by high recurrence rates and chemotherapy resistance. However, the metabolic heterogeneity and cell-specific metabolic profiles in TNBC remain underexplored. In this study, we analyzed the expression and prognostic impact of 87 metabolic pathways involving 1,668 genes, identifying 104 candidate metabolic checkpoint genes. Using consensus clustering, we uncovered two distinct metabolic subclusters of TNBC patients that exhibited significant differences in survival. We further characterized the differentially expressed genes, mutation profiles, and microenvironmental features between these two clusters. Additionally, <i>trans</i>-omics analysis of single-cell RNA sequencing revealed that <i>PLA2G4F</i>, a gene specifically expressed in malignant cells, functioned as a cell-autonomous metabolic reprogramming factor. We validated that <i>PLA2G4F</i> promotes the proliferation, migration, and survival of TNBC cells <i>in vitro</i>, driven by dysregulated glucose and lipid metabolism. These processes were mediated, at least in part, through the activation of the <i>AKT/PI3K</i> signaling pathway. This study highlights the metabolic heterogeneity in TNBC and identifies <i>PLA2G4F</i> as a pro-tumor factor, suggesting it as a potential novel therapeutic target.