Faecalibacterium prausnitzii suppresses ovarian cancer by inducing ferroptosis via phenylalanine metabolism activation.

Abstract

Ovarian cancer (OC) is a highly lethal gynecologic malignancy characterized by limited availability of treatment options and frequent recurrence. The gut microbiota has emerged as a key regulator of tumor progression; however, the anticancer potential of individual probiotic species remains insufficiently characterized and warrants further investigation. Ferroptosis is a regulated iron-dependent cell death with therapeutic potential in cancer. In this study, we initially observed that the traditional herbal pair, Scutellaria barbata D. Don (SB) and Scleromitrion diffusum (Wild) R.J. Wang (SD) exerted antitumor effects in a mouse model of OC, which was accompanied by a marked increase in the abundance of Faecalibacterium prausnitzii (F.prausnitzii) - a beneficial commensal bacterium not previously associated with cancer or ferroptosis. This observation prompted us to explore the functional role of F.prausnitzii in OC and revealed that it significantly suppressed ovarian tumor growth both in vitro and in vivo. Mechanistically, F.prausnitzii treatment elevated Fe²⁺ levels, increased lipid peroxidation, and depleted glutathione (GSH), which are hallmarks of ferroptosis. Transcriptomic analysis of tumor tissues from F.prausnitzii-treated mice identified ferroptosis and metal ion homeostasis pathways as major regulatory networks. Furthermore, metabolomic profiling revealed the activation of phenylalanine metabolism and increased production of phenylacetylglutamine (PAGln), suggesting a microbiota-metabolite axis contributing to ferroptosis induction. Our findings reveal that F.prausnitzii represents a novel ferroptosis-inducing probiotic with potent antitumor activity in OC. This study reveals a previously unrecognized role for this gut commensal and provides a mechanistic basis for the development of microbiota-based, ferroptosis-targeted therapeutic strategies in oncology.