Cervical cancer (CC) continues to pose a significant therapeutic challenge, ranking among the leading causes of morbidity and mortality in female reproductive malignancies. Cucurbitacin I (CuI), a natural compound, exhibits broad-spectrum anti-tumor activities, yet its effects and molecular mechanisms in CC remain unknown. This study aimed to investigate the anti-tumor efficacy of CuI in CC and to elucidate its underlying mechanisms. To confirm that CuI induces pyroptosis in tumor cells, gene downregulation/knockdown and selective inhibition approaches were used to comprehensively evaluate cellular morphological features, gasdermin (GSDM) protein cleavage, and the activation status of the TNF-caspase signaling pathway. Additionally, the synergistic effect of CuI in combination with cisplatin was examined through drug synergy experiments. Finally, a mouse subcutaneous xenograft model was conducted to evaluate the tumor inhibitory and immunomodulatory effects of the drug treatment. CuI effectively reduced the survival rate of CC cells. Mechanistically, CuI induces pyroptosis in cervical cancer cells, as evidenced by distinctive morphological features and GSDME cleavage. This cleavage is driven by enhanced caspase-8/3 activity downstream of TNFR1. Mechanistically, CuI activates the NF-κB pathway, which upregulates TNF-α secretion and subsequently triggers the TNFR1-caspase-8 cascade. Additionally, when combined with cisplatin, CuI enhanced pyroptosis, which in turn activated antitumor immunity and increased tumor suppression both in vitro and in vivo. CuI induces NF-κB/TNFR1/caspase-8/caspase-3/GSDME dependent pyroptosis and sensitizes cisplatin treatment in CC cells, which subsequently activates anti-tumor immune responses and contributes to tumor suppression in vivo.
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