Abstract
BACKGROUND: Wnt/β-catenin signaling drives many cancers; however, current inhibition strategies have limitations. Direct β-catenin inhibitors that block nuclear translocation represent an alternative therapeutic approach. We used colorectal cancer (CRC) as a study model, over 90% of the CRC cases harbor mutations in this pathway. Here, we aim to explore the potential of 15,16-dihydrotanshinone-I (DHTS) as a β-catenin inhibitor in cancer. METHODS: Molecular docking, biolayer interferometry assay and cellular thermal shift assay were used to examine the binding between DHTS and β-catenin. Site-directed mutagenesis, in vitro and in vivo studies were used to examine the anti-CRC effects of DHTS following its binding to β-catenin. RESULTS: We demonstrate, for the first time, that DHTS significantly reduces nuclear β-catenin levels and transcriptional activity in CRC without affecting β-catenin protein stability or conformation. DHTS binds to β-catenin at Ser411. A point mutation at Ser411 disrupts this binding and abolishes the ability of DHTS to suppress nuclear β-catenin, indicating that Ser411 binding is critical for blocking β-catenin nuclear translocation. Furthermore, we identify CD36, a transmembrane fatty acid translocase, as a downstream β-catenin target. DHTS reduces CD36 expression and cellular ATP levels in CRC cells; the reductions are reversed by β-catenin overexpression or stabilization. In CRC-bearing mouse model, DHTS-loaded PLGA-PEG nanoparticles significantly reduce nuclear β-catenin and CD36 expressions in tumors and inhibit tumor growth, consistent with the in vitro findings. CONCLUSIONS: Our study not only reveals the importance of Ser411 in β-catenin function but also paves the path for developing DHTS as a β-catenin inhibitor for CRC therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-07317-1.