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Cathepsin D (CTSD), a lysosomal hydrolase essential for \u03b1\u2010syn 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\u2010induced zebrafish and mouse PD models, as well as MPP+\u2010treated SH\u2010SY5Y cells, animals and cells were treated with Rg1 at different concentrations. Motor behavior, dopaminergic neuron survival, \u03b1\u2010syn 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 \u03b1\u2010syn 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\u2010ER homeostasis and counteracting multiple pathogenic pathways in PD. The findings reveal a CTSD\u2010dependent regulatory axis in \u03b1\u2010syn homeostasis and highlight Rg1 as a promising multi\u2010target therapeutic candidate for PD.<\/jats:p>","DOI":"10.1002\/ptr.70392","type":"journal-article","created":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T02:06:32Z","timestamp":1780711592000},"page":"5357-5373","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ginsenoside Rg1, a Natural Lysosomal Enhancer, Alleviates Parkinson's Disease Pathology via\n                    <scp>Cathepsin D<\/scp>\n                    \u2010Dependent Regulation of \u03b1\u2010Synuclein Homeostasis"],"prefix":"10.1002","volume":"40","author":[{"given":"Ya\u2010nan","family":"Fei","sequence":"first","affiliation":[{"name":"Faculty of Life Science and Technology Kunming University of Science and Technology  Kunming Yunnan 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