Objectives We aimed to investigate the antitumor effects of isoforsythiaside (IFY), a novel natural small compound, on osteosarcoma (OS) and breast cancer (BC), and to explore whether IFY exerts its activity by directly targeting the formin homology 2 domain (FH2) of dishevelled-associated activator of morphogenesis 1 (DAAM1). Methods Public data from The Human Protein Atlas (HPA) were analyzed for DAAM1 expression. Molecular docking (PyMOL) and microscale thermophoresis (MST) were used to confirm the direct binding of IFY to the FH2 domain of DAAM1 in vitro . Cell Counting Kit-8 (CCK8) assay, wound healing assay, Boyden chamber assay, Western blotting and microfilament assembly (immunofluorescence) were assessed in OS and BC cell lines. Antitumor efficacy was further evaluated in a 4T1 mouse breast cancer xenograft model. Results DAAM1 was highly expressed in OS and BC tissues and cells. IFY directly bound the FH2 domain of DAAM1. IFY (10-15 μmol/L) significantly reduced cell viability, migration, invasion, microfilament assembly, and DAAM1 protein expression levels in OS and BC cell lines. In vivo , IFY (10 mg/kg, i.p., q.2d) markedly suppressed tumor growth in BC-bearing mice. Conclusions IFY is a novel DAAM1 inhibitor that directly targets the FH2 domain and effectively suppresses the viability, motility, and microfilament assembly of OS and BC cells and inhibits tumor growth, suggesting its potential as a promising therapeutic candidate targeting the Wnt/PCP pathway.
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