Marine-Derived Fungal Metabolite MHO7 Promotes Breast Cancer Apoptosis as a Hippo Pathway Regulator by Modulating the YAP-TEAD Axis.

Breast cancer, especially triple-negative breast cancer (TNBC) and endocrine-resistant disease, remains difficult to treat because of limited effective targeted therapies. In this study, we evaluated the antitumor activity and potential mechanism of MHO7, a marine-derived ophiobolin metabolite, in ER-positive ZR-75-30 cells, tamoxifen-resistant LCC2 cells, and TNBC MDA-MB-231 models. MHO7 dose-dependently reduced cell viability, wound closure, and clonogenic growth in ZR-75-30 and LCC2 cells, with IC50 values of 11.53 and 10.43 μM, respectively. MHO7 also promoted apoptotic cell death, accompanied by increased reactive oxygen species accumulation and altered expression of apoptosis-related proteins, including Bcl-2 and caspase-3. N-acetyl-L-cysteine partially attenuated MHO7-induced apoptosis and YAP reduction in MDA-MB-231 cells, suggesting a contribution of oxidative stress. Molecular docking predicted that MHO7 could occupy the conserved TEAD palmitoylation pocket, and subsequent in vitro analyses showed suppression of YAP/TAZ-TEAD signaling, including reduced YAP nuclear accumulation and decreased TEAD4 expression. In an MDA-MB-231 xenograft model, MHO7 significantly inhibited tumor growth, reduced CD31-positive microvessel density, and decreased Hippo pathway-related transcriptional readouts. These findings indicate that MHO7 exerts broad antitumor activity in breast cancer models through oxidative stress-associated apoptosis and modulation of YAP/TAZ-TEAD signaling, supporting its further development as a lead compound for treatment-resistant breast cancer.