GLUL drives metabolic reprogramming and confers docetaxel resistance in prostate cancer.

Docetaxel is a first-line chemotherapeutic agent for advanced and castration-resistant prostate cancer (CRPC), yet acquired resistance limits its long-term efficacy. Metabolic reprogramming has emerged as a central mechanism of therapeutic resistance; however, the metabolic determinants of docetaxel resistance remain incompletely defined. Here, we identify glutamate-ammonia ligase (GLUL), the key enzyme mediating de novo glutamine synthesis, as a critical regulator of docetaxel resistance. Integrated transcriptomic, metabolomic, and single-cell RNA sequencing analyses of clinical specimens revealed significant enrichment of amino acid metabolic pathways, with glutamine metabolism as a dominant alteration. GLUL was consistently upregulated in resistant tumors and validated across independent cohorts. High GLUL expression was associated with activation of PI3K-AKT-mTOR signaling, glycolysis, and oxidative phosphorylation. Functionally, GLUL overexpression enhanced glutamine metabolic flux, promoted cell cycle progression, suppressed docetaxel-induced apoptosis, and increased cell viability under treatment. Conversely, GLUL knockdown restored chemosensitivity in resistant cells and significantly suppressed tumor growth in xenograft models. Mechanistically, GLUL-driven metabolic reprogramming reshaped bioenergetic and redox homeostasis and was tightly coupled to pro-survival signaling activation, forming a coordinated metabolism-signaling network that supports chemoresistance. Collectively, these findings establish GLUL as a key metabolic driver of docetaxel resistance and highlight glutamine synthesis as a pharmacologically actionable vulnerability in CRPC.