Lycorine suppresses cell growth and attenuates stemness through PI3K/AKT pathway in ovarian cancer

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.