Ovarian cancer is one of the most lethal gynecological diseases owing to its poor prognosis and lack of clear symptoms. Cisplatin is commonly used as the primary chemotherapeutic drug for ovarian cancer. However, chemoresistance to cisplatin in advanced ovarian cancer is a major factor contributing to chemotherapy failure. Pyruvate kinase M2 (PKM2) is significantly upregulated in ovarian cancer tissues, thereby contributing to cisplatin resistance. Despite this, its therapeutic role remains unclear. This study aimed to evaluate whether shikonin and compound 3K, PKM2 inhibitor, could enhance anticancer effects in cisplatin-resistant ovarian cancer SKOV-3 cells by regulating autophagic pathways. Cytotoxicity assays using MTT and colony formation assays demonstrated that shikonin or compound 3K treatment significantly reduced PKM2 expression in SKOV-3 cells. Shikonin and compound 3K inhibited PKM2-mediated glycolysis and induced autophagic cell death in cisplatin-resistant ovarian cancer cells, resulting in significant suppression of cell proliferation and survival. Additionally, Shikonin and compound 3K treatment suppressed PKM2-mediated glycolysis and induced autophagic cell death in cisplatin-resistant ovarian cancer cells, as evidenced by increased LC3-II expression, autophagosome formation, and reduced cell viability. These findings strongly suggest that PKM2 overexpression plays a key role in cisplatin resistance in ovarian cancer. Thus, PKM2 inhibitors use may be a highly effective strategy for overcoming chemoresistance and improving outcomes in patients with advanced ovarian cancer.

Ovarian cancer is among the most lethal gynecological malignancies due to its poor prognosis and lack of early symptoms. Cisplatin remains the primary chemotherapeutic agent; however, resistance to cisplatin in advanced ovarian cancer is a major cause of treatment failure. Pyruvate kinase M2 (PKM2) is markedly upregulated in ovarian cancer tissues and contributes to cisplatin resistance, though its therapeutic relevance has not been fully defined. This study investigated whether shikonin and compound 3K, both PKM2 inhibitors, could enhance anticancer effects in cisplatin-resistant SKOV-3 cells by modulating autophagic pathways. Cytotoxicity assays revealed that treatment with shikonin or compound 3K significantly reduced PKM2 expression. Combination therapy with high-dose PKM2 inhibitors and cisplatin increased apoptosis compared to controls, although the modest induction suggests apoptosis is only partially responsible for the observed effects. Additionally, Shikonin and compound 3K treatment suppressed PKM2-mediated glycolysis and induced autophagic cell death in cisplatin-resistant ovarian cancer cells, as evidenced by increased LC3-II expression, autophagosome formation, and reduced cell viability. These findings indicate that PKM2 overexpression plays a central role in cisplatin resistance in ovarian cancer. Targeting PKM2 with inhibitors such as shikonin or compound 3K may represent a promising strategy to overcome chemoresistance and improve therapeutic outcomes in patients with advanced ovarian cancer. These findings strongly suggest that PKM2 overexpression plays a key role in cisplatin resistance in ovarian cancer. Thus, PKM2 inhibitors use may be a highly effective strategy for overcoming chemoresistance and improving outcomes in patients with advanced ovarian cancer.