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.