Ginsenoside Rg1, a Natural Lysosomal Enhancer, Alleviates Parkinson's Disease Pathology via Cathepsin D ‐Dependent Regulation of α‐Synuclein Homeostasis

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss and α‐synuclein (α‐syn) aggregation, often linked to lysosomal dysfunction. Cathepsin D (CTSD), a lysosomal hydrolase essential for α‐syn clearance, becomes functionally impaired when its maturation is disrupted, exacerbating proteostatic stress. This study investigated whether ginsenoside Rg1(Rg1) restores CTSD maturation and lysosomal function to mitigate PD pathology. MPTP‐induced zebrafish and mouse PD models, as well as MPP+‐treated SH‐SY5Y cells, animals and cells were treated with Rg1 at different concentrations. Motor behavior, dopaminergic neuron survival, α‐syn clearance, CTSD maturation, lysosomal activity, endoplasmic reticulum (ER) stress, oxidative stress, autophagic flux, and apoptosis were systematically evaluated. Rg1 improved locomotor performance and preserved dopaminergic neurons, promoted α‐syn clearance, and enhanced CTSD maturation in lysosomes. These effects coincided with reduced ER and oxidative stress, normalized autophagic flux, and decreased apoptosis. Rg1 functions as a natural lysosomal enhancer, restoring lysosome‐ER homeostasis and counteracting multiple pathogenic pathways in PD. The findings reveal a CTSD‐dependent regulatory axis in α‐syn homeostasis and highlight Rg1 as a promising multi‐target therapeutic candidate for PD.