Deciphering glutamine metabolic reprogramming: a novel therapeutic target ALDH18A1 in triple-negative breast cancer

Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype with limited therapeutic options and poor prognosis, highlighting an urgent need to identify novel metabolic vulnerabilities and prognostic biomarkers to improve patient outcomes. While glutamine metabolism has been implicated in cancer, the specific roles of glutamine metabolism-related genes (GMRGs) in TNBC remain poorly understood. Herein, through an integrating analysis encompassing multi-omics bioinformatics, consensus clustering and tumor microenvironment (TME) analysis, we established a glutamine metabolism-based prognostic classification for TNBC patients, which correlates with distinct survival outcomes and TME features. Furthermore, we identified ALDH18A1, one of the GMRGs that encodes P5CS for proline synthesis, as a novel prognostic biomarker and oncogenic driver. ALDH18A1 is overexpressed in TNBC and associated with larger tumor size, lymph node metastasis and poor survival, as well as an immunosuppressive TME. In vitro experiments confirmed ALDH18A1 activated the AKT/mTOR signaling pathway, promoted the proliferation, migration and invasion of TNBC cells, and increased proline synthesis. Computational drug screening predicted six compounds with potential efficacy against ALDH18A1-high tumors. Collectively, our findings demonstrate that reprogramming of glutamine metabolism plays a crucial role in the malignant progression of TNBC and provide translational insights for precision metabolomic-immunotherapeutic strategies in ALDH18A1-high TNBC.