Cutibacterium acnes-Derived Extracellular Vesicles Promote Epithelial Ovarian Cancer Progression by Activating the KEAP1-NRF2 Antioxidant Pathway to Suppress Ferroptosis.

Bacterial extracellular vesicles are increasingly recognized as important mediators of microbe-host communication, yet their functional roles within tumour-associated microbiota remain poorly understood. Here, we investigated whether extracellular vesicles derived from Cutibacterium acnes (CEVs) regulate host redox metabolism and ferroptosis in epithelial ovarian cancer (EOC). Using integrated in vitro and in vivo models, we found that CEVs significantly promoted tumour growth and induced transcriptional reprogramming toward antioxidant defence and ferroptosis resistance. Mechanistically, CEVs activated the KEAP1-NRF2 signalling axis through coordinated downregulation of ACSL4 and KEAP1, leading to enhanced glutathione biosynthesis, increased GPX4 activity, reduced lipid peroxidation and decreased intracellular reactive oxygen species levels. These metabolic alterations suppressed ferroptosis and promoted tumour cell survival. Importantly, pharmacological induction of ferroptosis using RSL3 abolished the tumour-promoting effects of CEVs, demonstrating that ferroptosis suppression is essential for CEVs-mediated tumour progression. Collectively, our findings identify bacterial extracellular vesicles as functional modulators of host redox metabolism and ferroptosis, revealing a previously unrecognized mechanism by which tumour-associated microbiota influence cancer progression.