Abstract

Ovarian cancer remains the most lethal gynecological malignancy worldwide, largely owing to poor prognosis associated with chemotherapy resistance and cancer stem cell-driven recurrence. This study comprehensively investigates the antitumor effects of lycorine, a natural alkaloid derived from Lycoris radiata , in human ovarian cancer models. Our results demonstrate that lycorine significantly inhibits ovarian cancer cell proliferation, induces apoptosis, and suppresses cancer stemness through modulation of the PI3K/AKT signaling pathway. In vitro, lycorine treatment reduced the expression of stemness-associated markers ( CD133 , CD44 , NANOG , SOX2 , OCT4 , and LIN28A ) by approximately 30–80% and impaired tumor sphere formation by more than 75%. RNA sequencing and pathway enrichment analysis confirmed significant suppression of the PI3K/AKT signaling pathway, accompanied by reduced phosphorylation of AKT and mTOR. In vivo, lycorine (5 mg/kg) effectively suppressed tumor growth by approximately 75% in A2780-luc xenograft models, reduced cancer stem cell subpopulations, and exhibited minimal systemic toxicity. Furthermore, lycorine sensitized ovarian cancer cells to cisplatin and counteracted cisplatin-induced enrichment of cancer stem cell populations. These findings highlight lycorine as a promising multi-target therapeutic agent for ovarian cancer, particularly in addressing stemness-driven chemoresistance and tumor recurrence.