Biochanin A exerts neuroprotective effects in Parkinson's disease both in vivo and in vitro by improving mitochondrial dysfunction through the Sirt1 signaling pathway.

The accumulation of reactive oxygen species (ROS) leading to mitochondrial dysfunction is the pathological characteristics underlying the damage to dopaminergic neurons in the substantia nigra (SN) of Parkinson's disease (PD). Therefore, through improving mitochondrial dysfunction may be a potential strategy for PD treatment. Biochanin A (Bioch A), as a natural isoflavone phytoestrogen, has been implicated in studies for its therapeutic potential in neurodegenerative diseases. However, the precise molecular mechanisms by which it modulates PD-related neuronal damage remain unclear, limiting its clinical translational application. This study focuses on the neuroprotective mechanism of Bioch A, systematically revealing the key pathways and regulatory mechanisms through which it exerts its neuroprotective effects in PD by targeting mitochondrial dysfunction. By establishing lipopolysaccharide (LPS)-induced PD model mice and tumor necrosis factor-α (TNF-α)-induced SH-SY5Y cell models, combined with in vivo and in vitro experiments confirmed that Bioch A significantly alleviates dopaminergic neuronal damage by downregulating ROS levels, modulating adenosine triphosphate (ATP) production, promoting mitochondrial biogenesis, and improving abnormal mitochondrial dynamics. More importantly, this study has for the first time revealed that the Sirt1 pathway is a core target for Bioch A in regulating mitochondrial dysfunction. Furthermore, Bioch A promotes mitochondrial biogenesis by activating the Sirt1 pathway and reduces apoptosis levels by promoting mitochondrial fusion. In conclusion, this study provides novel experimental evidence for Bioch A's regulation of mitochondrial dysfunction, establishing the Sirt1 pathway as a key neuroprotective target. This discovery paves the way for Bioch A's clinical translation and targeted therapeutic research in PD.