This preclinical study shows that formononetin, a phytoestrogen, alleviates MPP+/MPTP-induced neurotoxicity and motor deficits by activating the SIRT1/PGC-1α/NRF1/TFAM axis to restore mitochondrial biogenesis, reduce ROS, and preserve mitochondrial integrity in SH-SY5Y cells and MPTP mice.

By providing in vitro and in vivo evidence that a small natural compound can pharmacologically restore mitochondrial biogenesis and function via a defined SIRT1/PGC-1α pathway, the study offers an actionable therapeutic lead and biomarker axis for PD drug discovery, while translation will require…

Parkinson's disease (PD) is a progressive neurodegenerative disorder. An essential early hallmark of PD is disrupted mitochondrial dynamics driven by impaired cellular energy homeostasis. Therapeutic interventions restoring mitochondrial function and biogenesis hold promise for neuroprotection in PD. In the present study, the neuroprotective effects of formononetin (FMN) were evaluated in both MPP+-induced SH-SY5Y cells and the MPTP-induced mouse model of Parkinson's disease, using concentrations of 5, 10, 20, and 40 μM in vitro and doses of 25 and 40 mg/kg in vivo. To evaluate its biological activity, we employed western blotting and immunofluorescence assay to quantify the expression of disease-relevant markers. Mitochondrial health was further assessed using Mitotracker, alongside reactive oxygen species (ROS) assessment. Motor behavior and molecular endpoint parameters were also measured. Our results demonstrated that FMN significantly attenuates MPP+/MPTP-induced neurotoxicity, improves motor function, and restores the expression of PGC-1α, tyrosine hydroxylase, and key mitochondrial proteins involved in mitochondrial DNA replication. Enhancement of mitochondrial fusion proteins and other transcriptional regulators was also observed in the administered groups. Flow cytometry and imaging analyses confirmed that FMN-mediated PGC-1α activation preserves mitochondrial integrity and reduces oxidative stress. Altogether, these findings provide evidence that formononetin exerts neuroprotective effects in PD by modulating the PGC-1α signaling axis.