Honokiol Suppresses Stemness and Sensitizes Triple-Negative Breast Cancer to Chemotherapy via YAP/TAZ-TEAD Inhibition.

Abstract

Objectives: As an aggressive subtype of breast cancer, triple-negative breast cancer (TNBC) is constrained by the limited availability of effective treatments and the absence of well-validated therapeutic targets. This study aimed to explore whether honokiol, a potent YAP/TAZ inhibitor, suppresses stem cell-like properties and enhances chemotherapeutic efficacy in TNBC by blocking YAP/TAZ-TEAD transcriptional complex. Methods: Through both in vitro and in vivo models of TNBC, the current study examined how honokiol influences cell proliferation, cancer stem cell (CSC) traits, and paclitaxel sensitivity. To uncover the molecular mechanisms, we analyzed the transcript levels and protein abundance of core YAP/TAZ-TEAD pathway members, including YAP, TAZ, TEADs, ANKRD1, and CYR61. Furthermore, we conducted immunofluorescence staining to examine the nuclear localization of YAP/TAZ. Potential direct interactions were identified using molecular docking, which also predicted the binding affinity between honokiol and the TAZ-TEAD complex. Results: Honokiol markedly suppressed the viability and stemness of TNBC cells. It also improved the antitumor efficacy of paclitaxel in both TNBC cells and xenograft models. Mechanistically, honokiol may directly target the TAZ-TEAD complex, as indicated by molecular docking analysis. This interaction led to decreased YAP/TAZ protein levels and blockade of their nuclear accumulation, thereby suppressing the downstream transcriptional targets ANKRD1 and CYR61 in TNBC cells. Conclusion: Collectively, our findings suggest that honokiol is a promising therapeutic agent against TNBC, acting at least in part by suppressing the transcriptional activity of the YAP/TAZ-TEAD complex, thus attenuating cancer stemness and overcoming chemoresistance. These findings highlight honokiol's translational potential.