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Through a comprehensive screening and validation process involving multiple\u00a0models, ginsenoside Rg3 (Rg3) as a compound capable of enhancing cardiolipin levels is identified. This augmentation in cardiolipin levels fosters mitochondrial homeostasis by bolstering mitochondrial unfolded protein response, promoting mitophagy, and enhancing mitochondrial oxidative phosphorylation. Consequently, this cascade enhances the survival of tyrosine hydroxylase positive (TH\n                    <jats:sup>+<\/jats:sup>\n                    ) dopaminergic neurons, leading to an amelioration in motor performance within PD mouse models. Using limited proteolysis\u2013small\u2010molecule mapping combined with molecular docking analysis, it has confirmed Growth Factor Receptor\u2010Bound Protein 2 (GRB2) as a molecular target for Rg3. Furthermore, these investigations reveal that Rg3 facilitates the interaction between GRB2 and TRKA (Neurotrophic Tyrosine Kinase, Receptor, Type 1), thus promotes EVI1 (Ecotropic Virus Integration Site 1 Protein Homolog) phosphorylation by ERK, subsequently increases CRLS1 (Cardiolipin Synthase 1) gene expression and boosts cardiolipin synthesis. The absence of GRB2 or CRLS1 significantly attenuates the beneficial effects of Rg3 on PD symptoms. Finally, Tenofovir Disoproxil Fumarate (TDF) that also promotes the binding between GRB2 and TRKA is further identified. The identified compounds, Rg3 and TDF, exhibit promising potential for the prevention of PD by bolstering cardiolipin expression and reinstating mitochondrial homeostasis.\n                  <\/jats:p>","DOI":"10.1002\/advs.202403058","type":"journal-article","created":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T14:24:51Z","timestamp":1724077491000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Ginsenoside Rg3 Restores Mitochondrial Cardiolipin Homeostasis via GRB2 to Prevent Parkinson's Disease"],"prefix":"10.1002","volume":"11","author":[{"given":"Li\u2010Feng\u2010Rong","family":"Qi","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing Jiangsu 210009 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing Jiangsu 210009 China"},{"name":"Department of Pharmacy The Fourth Affiliated Hospital Center for Innovative Traditional Chinese Medicine Target and New Drug Research International Institutes of Medicine Zhejiang University School of Medicine  Yiwu Zhejiang 322000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuyuan","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Biophysics and Department of Neurosurgery of the First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou Zhejiang 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Qian","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing Jiangsu 210009 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Peng","sequence":"additional","affiliation":[{"name":"National Facility for Protein Science in Shanghai Zhangjiang Lab Shanghai Advanced Research Institute Chinese Academy of Science  Shanghai 201210 China"},{"name":"Shanghai Science Research Center Chinese Academy of Sciences  Shanghai 201204 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuci","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing Jiangsu 210009 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing Jiangsu 210009 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Wu","sequence":"additional","affiliation":[{"name":"National Facility for Protein Science in Shanghai Zhangjiang Lab Shanghai Advanced Research Institute Chinese Academy of Science  Shanghai 201210 China"},{"name":"Shanghai Science Research Center Chinese Academy of Sciences  Shanghai 201204 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Shan","sequence":"additional","affiliation":[{"name":"Dept. 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