Targeting FGFR1 with aloperine suppresses angiogenesis, vasculogenic mimicry, and metastasis in triple-negative breast cancer

Background Triple-negative breast cancer (TNBC) is a highly aggressive malignancy characterized by early recurrence and high metastatic potential. Its aggressiveness is driven by a complex vascular network integrating classical angiogenesis and vasculogenic mimicry (VM). Despite the clinical implementation of PARP inhibitors and immune checkpoint blockade, effective targeted therapeutic strategies remain limited for the majority of TNBC patients. Methods The effects of aloperine on angiogenesis were analyzed using a panel of in vitro assays in human umbilical vein endothelial cells (HUVECs), ex vivo aortic ring assays, and in vivo Matrigel plug assays. Its effects on TNBC cell migration and VM formation were assessed in MDA-MB-231 cells using Transwell migration and tube formation assays, respectively. Mechanistic studies were performed using Western blotting, molecular docking, and cell-free kinase assays. Finally, the therapeutic efficacy of aloperine against TNBC progression was validated in a mouse dorsal skinfold chamber model of murine 4T1 tumors and an orthotopic xenograft model of human MDA-MB-231 tumors. Results In this study, we identified aloperine, a natural quinolizidine alkaloid, as a multimodal inhibitor of TNBC progression. Aloperine preferentially suppressed endothelial angiogenesis as well as TNBC cell migration and VM formation at concentrations with minimal effects on tumor cell proliferation. Mechanistically, aloperine directly bound to the ATP-binding pocket of fibroblast growth factor receptor 1 (FGFR1), thereby inhibiting its kinase activity and downstream Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling in both endothelial and tumor cells. In vivo , aloperine effectively suppressed tumor angiogenesis, VM, and metastasis in both murine and human TNBC models. Conclusions These findings demonstrate that aloperine disrupts the dual vascular supply and metastatic progression of TNBC by selectively targeting the FGFR1/JAK2/STAT3 signaling axis, positioning aloperine as a promising therapeutic candidate and FGFR1 as a compelling target for TNBC treatment.