Formononetin derived from Parabacteroides merdae alleviates MPTP-induced Parkinson's disease in mice by inhibiting ferroptosis via the PI3K-AKT-ferritinophagy axis

Parkinson's disease (PD) is a prevalent neurological disorder that has been increasingly linked to gut dysbiosis. However, the mechanisms by which gut microbiota regulate the pathogenesis of PD remain unclear. In this study, we model PD in male mice via MPTP-induction, and demonstrate a significant reduction in the intestinal abundance of Parabacteroides merdae (P. merdae). Administration of P. merdae to these mice alleviates MPTP-induced PD symptoms. Furthermore, P. merdae mitigates MPTP-induced PD by releasing formononetin (FMN) through b-galactosidase (b-GAL) activity. Both P. merdae and FMN administration inhibits MPTP-induced ferroptosis during PD progression. Blocking ferroptosis using ferrostatin-1 or ACSL4 knock-down also ameliorated MPTP-induced PD in mice. Mechanistically, FMN activates the PI3K-AKT pathway, which suppressed ferroptosis by restoring FTH levels via regulation of NCOA4-mediated ferritinophagy. Collectively, our findings reveal that P. merdae-derived FMN alleviates MPTP-induced PD by inhibiting ferroptosis via the PI3K-AKT-NCOA4-ferritinophagy axis, highlighting the potential therapeutic strategy for PD intervention based on modulating gut microbiota-mediated FMN release and ferroptosis.