Bifidobacterium animalis subsp. lactis delays epithelial ovarian cancer progression by secreting acetate and regulating the NRF2–HO-1–ferroptosis pathway

Recent advances have highlighted the anti-tumour effects exerted by the gut microbiota and its derived metabolites through modulation of ferroptosis; however, their role in epithelial ovarian cancer (EOC) has not been fully explored. Based on qPCR analysis and previous 16S rRNA sequencing data, we first identified Bifidobacterium as being markedly depleted in the gut microbiota of females with EOC. Acetic acid, a key bacterial metabolite, was also found to differ significantly between EOC and control groups in both humans and mice, as determined by gas chromatography–mass spectrometry (GC-MS). Through oral gavage of Bifidobacterium animalis subsp. lactis NCU-01 and sodium acetate in an EOC mouse model, their inhibitory effects on tumour growth, restoration of intestinal barrier function, and attenuation of systemic inflammation were validated. Haematoxylin and eosin staining and transmission electron microscopy revealed distinctive ferroptosis-related features in tumour cells, including cytoplasmic deep staining and mitochondrial cristae degeneration. Western blotting and ELISA further demonstrated disruption of iron homoeostasis regulators TFR1 and FTH1, alterations in lipid peroxidation and oxidative stress markers (MDA, GSH and SOD), and downregulation of the NRF2/HO-1/GPX4 signalling cascade that counteracts ferroptosis in EOC tissues. Overall, this study reveals a previously unrecognised microbiota–metabolite axis centred on NRF2/HO-1/GPX4 signalling that balances ferroptosis and antioxidant defence, providing a potential therapeutic strategy for EOC intervention and underscoring the translational promise of probiotics in precision oncology.