Glioblastoma (GBM), the most aggressive primary brain malignancy, presents an urgent need for novel therapeutic targets addressing metabolic reprogramming in tumor progression. Natural product-based molecular probes have emerged as powerful tools for target discovery and mechanistic elucidation in cancer biology. Here, we identified the fungal polyketide auxarconjugatin B (AUX-B) as a potent inhibitor of GBM proliferation through both in vitro and in vivo models. Chemical biology strategies revealed secretory carrier membrane protein 2 (SCAMP2) as the covalent cellular target of AUX-B. SCAMP2 exhibited significant overexpression in human GBM specimens and orthotopic GBM mouse models, correlating with tumor progression. Mechanistic investigations demonstrated that SCAMP2 orchestrates metabolic reprogramming through the regulation of aspartate transporters (solute carrier family 1 member 3 and solute carrier family 25 member 12) and asparagine synthetase, thereby sustaining aspartate metabolic flux critical for GBM growth. AUX-B-mediated reduction of SCAMP2 effectively disrupted this pathogenic metabolic network, leading to a decrease in intracellular aspartate levels. Our findings establish SCAMP2 as a novel therapeutic target in GBM and characterize AUX-B as a new SCAMP2 inhibitor with translational potential through metabolic modulation.

Auxarconjugatin B  /  Glioblastoma  /  SCAMP2  /  ABPP  /  Aspartate  /  Metabolic flux  /  Aspartate transporters  /  SLC1A3