Combination of Tripterygium glycosides and Lactobacillus paracasei sensitises epithelial ovarian cancer to cisplatin via downregulating Keap1-Nrf2-GPX4 signalling pathway

Abstract Background Epithelial ovarian cancer (EOC) is a highly heterogeneous malignancy with significant morbidity and mortality, and cisplatin (DDP) resistance remains a major obstacle in its treatment. Previous studies suggest that Tripterygium glycosides (TG), derived from Tripterygium wilfordii, may enhance EOC chemo-sensitivity to DDP, potentially involving gut microbiota, though the underlying mechanisms remain to be fully elucidated. Purpose This study sought to determine how TG enhanced chemotherapy sensitivity in EOC and to examine the involvement of gut microbiota in this process. Study design Experimental research in vivo models was conducted, including fecal microbiota transplantation (FMT) from healthy controls and validation assays with Lactobacillus paracasei. Methods TG were administered alone or combined with FMT to evaluate their impact on DDP sensitivity in EOC. Mechanistic studies focused on the Keap1–Nrf2–GPX4 signalling pathway and ferroptosis induction. L. paracasei was co-administered with TG to assess synergistic effects, while Nrf2 pathway activation was tested to confirm its regulatory role. Results TG significantly enhanced DDP sensitivity in EOC, either alone or synergistically with FMT. Mechanistically, TG inhibited the Keap1–Nrf2–GPX4 axis, inducing tumor ferroptosis. Gut microbiota, particularly the probiotic Lactobacillus, contributed to this effect: L. paracasei combined with TG amplified DDP cytotoxicity in EOC cells. Conversely, Nrf2 pathway activation attenuated the synergistic effect. Conclusion TG sensitises EOC to DDP by suppressing the Keap1–Nrf2–GPX4 pathway to trigger ferroptosis, with gut microbiota (e.g., L. paracasei) playing a synergistic role. Combining TG and probiotics may offer a promising and innovative method to improve chemotherapy efficacy in EOC, offering a foundation for future therapeutic development. Graphical abstract