Paris polyphylla saponin Ⅱ induces autophagy-associated ferroptosis by regulating the BECLIN1/SLC7A11 axis in cervical cancer.

Cervical cancer remains a lethal gynecologic malignancy requiring novel therapies. Here, we investigated the antitumor mechanism of Paris polyphylla saponin Ⅱ (PPSⅡ) in vitro and in vivo. PPSⅡ suppressed proliferation and induced cell death in SiHa, U14, and HeLa cells. The ferroptosis inhibitor ferrostatin-1 (Fer-1) and the autophagy inhibitor chloroquine (CQ) both partially reversed PPSⅡ-induced cell death, indicating involvement of both pathways. Mechanistically, SLC7A11 overexpression reversed the effects of PPSⅡ on GPX4 and ACSL4 expression, whereas BECLIN1 knockdown altered SLC7A11 expression, suggesting that PPSⅡ acts via the BECLIN1/SLC7A11 axis to induce autophagy-dependent ferroptosis. In a HeLa xenograft mouse model, PPSⅡ (1 or 2 mg/kg) significantly reduced tumor volume and weight. Immunohistochemistry showed decreased Ki-67 positivity, and H&E staining revealed tumor necrosis comparable to cisplatin. Notably, PPSⅡ caused no significant pathological changes in heart, liver, spleen, lungs, or kidneys, whereas cisplatin induced renal tubular vacuolation and hepatic inflammation, indicating a better safety profile. In conclusion, PPSⅡ induces autophagy-dependent ferroptosis in cervical cancer cells by modulating the BECLIN1/SLC7A11 pathway and shows potent in vivo antitumor efficacy with low toxicity. These results support PPSⅡ as a promising candidate for cervical cancer therapy.