Miltirone suppresses proliferation and induces apoptosis in ovarian cancer cells in association with modulation of the RBM15/E2F2/PI3K/Akt signaling axis

Ovarian cancer (OC) is a lethal malignancy with limited treatment due to chemoresistance and recurrence, necessitating new agents. Miltirone has anti-tumor activity in other cancers, but its role in OC is unknown. This study investigated miltirone’s effects on OC cells and underlying mechanisms. We assessed proliferation, migration, invasion, and apoptosis using CCK-8, colony formation, wound healing, Transwell, and TUNEL assays. Molecular docking predicted miltirone-RBM15 binding; Western blot analyzed RBM15/E2F2/PI3K/Akt proteins. Functional rescue experiments employed siRNA-mediated knockdown and lentivirus-mediated overexpression of RBM15. Finally, a nude mouse xenograft model was used to assess miltirone’s in vivo anti-tumor efficacy. Miltirone dose-dependently inhibited OC cell proliferation, migration, invasion, and induced apoptosis. It downregulated RBM15, E2F2, and PI3K/Akt phosphorylation. RBM15 knockdown mimicked miltirone’s anti-tumor effects, while overexpression partially reversed them. In vivo, miltirone suppressed tumor growth, reduced Ki67-positive cells, increased apoptosis, and downregulated the RBM15/E2F2/PI3K/Akt axis. This first report demonstrates that miltirone inhibits OC progression and induces apoptosis in association with modulation of the RBM15/E2F2/PI3K/Akt axis, positioning miltirone as a preclinical lead compound and this axis as a novel therapeutic target.