FOXC1–GMDS axis-driven glycolytic reprogramming promotes tumor progression in triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is a clinically aggressive subtype that is highly reliant on glycolytic metabolism. Despite this well-characterized metabolic feature, the molecular mechanisms governing glycolytic fitness and the therapeutic potential to exploit these metabolic adaptations remain poorly defined. In this study, we pinpoint GDP-mannose 4,6-dehydratase (GMDS) as a transcriptionally regulated metabolic effector that sustains glycolytic fitness and promotes tumorigenesis and progression in TNBC. Multiomic analyses converge to identify GMDS as a pivotal metabolic node in TNBC, while mechanistic investigations demonstrate that the transcription factor FOXC1 drives GMDS expression by directly binding to its promoter region. GMDS induces a glycolytic metabolic state via the cAMP/PKA-CREB-PFKFB2 signaling axis, thereby enhancing the proliferative and metastatic capacities of TNBC cells. Genetic ablation of GMDS impairs glycolytic flux and potently inhibits tumor growth, defining GMDS as a critical metabolic dependency in TNBC. Furthermore, structure-guided screening yields a candidate GMDS inhibitor that recapitulates the phenotypic effects of GMDS depletion and effectively inhibits the progression of TNBC, revealing a pharmacologically actionable metabolic vulnerability. Collectively, our findings establish a FOXC1-GMDS metabolic axis that connects lineage-specific transcriptional control to glycolytic rewiring, and position GMDS as a druggable metabolic effector and precision therapeutic target in TNBC.