Natural product cephalomannine suppresses triple-negative breast cancer progression by targeting VEGFR1 signaling.

Cephalomannine (CPM), a naturally occurring taxane isolated from Taxus wallichiana, exhibits broad antitumor activity against multiple solid malignancies. However, the molecular targets responsible for this anticancer activity remain poorly defined. Here, we used an integrated chemical-genomic and functional framework to elucidate the molecular basis of CPM action in triple-negative breast cancer (TNBC). High-throughput perturbational transcriptomic profiling, computational target prediction, structural molecular modeling, and biophysical validation have converged to identify vascular endothelial growth factor receptor 1 (VEGFR1) as a key molecular determinants of CPM. Functional analysis showed that CPM potently suppressed TNBC cell proliferation and migration at nanomolar concentrations and significantly inhibited tumor growth and metastatic dissemination in orthotopic xenograft models. Mechanistically, CPM selectively attenuated VEGFR1-dependent Src/β-catenin signaling and epithelial-mesenchymal transition (EMT) programs without altering the total receptor abundance, consistent with a non-canonical, phosphorylation-dependent mode of action. Collectively, these findings establish a previously unrecognized mechanism by which CPM exerts its antitumor and anti-metastatic effects in TNBC, expand the current understanding of taxane pharmacology, and provide a rational foundation for the development of VEGFR1-targeted CPM-based therapeutic strategies for aggressive treatment-refractory breast cancers.