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Despite extensive research, a definitive cure remains elusive. Eucommia ulmoides Oliv. leaves (EUOL) have been reported to exhibit protective effects on neurodegenerative diseases, however, their efficacy, key active constituents, and pharmacological mechanisms are not yet understood. This study aims to explore the optimal constituents of EUOL regarding anti-PD activity and its underlying mechanisms. Using a zebrafish PD model, we found that the 30% ethanol fraction extract (EF) of EUOL significantly relieved MPTP-induced locomotor impairments, increased the length of dopaminergic neurons, inhibited the loss of neuronal vasculature, and regulated the misexpression of autophagy-related genes (\u03b1-syn, lc3b, p62, and atg7). Assays of key regulators involved in PD further verified the potential of the 30% EF against PD in the cellular PD model. Reverse phase protein array (RPPA) analysis revealed that 30% EF exerted anti-PD activity by activating 4E-BP1, which was confirmed by Western blotting. Phytochemical analysis indicated that cryptochlorogenic acid, chlorogenic acid, asperuloside, caffeic acid, and asperulosidic acid are the main components of the 30% EF. Molecular docking and surface plasmon resonance (SPR) indicated that the main components of the 30% EF exhibited favorable binding interactions with 4E-BP1, further highlighting the roles of 4E-BP1 in this process. Accordingly, these components were observed to ameliorate PD-like behaviors in the zebrafish model. Overall, this study revealed that the 30% EF is the key active constituent of EUOL, which had considerable ameliorative effects on PD by up-regulating 4E-BP1. This suggests that EUOL could serve as a promising candidate for the development of novel functional foods aimed at supporting PD treatment.<\/jats:p>","DOI":"10.3390\/ijms26062762","type":"journal-article","created":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T07:48:37Z","timestamp":1742370517000},"page":"2762","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of Key Active Constituents in Eucommia ulmoides Oliv. Leaves Against Parkinson\u2019s Disease and the Alleviative Effects via 4E-BP1 Up-Regulation"],"prefix":"10.3390","volume":"26","author":[{"given":"Yuqing","family":"Li","sequence":"first","affiliation":[{"name":"Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 East Jingshi Road, Jinan 250103, China"},{"name":"Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, 28789 East Jingshi Road, Jinan 250103, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruidie","family":"Shi","sequence":"additional","affiliation":[{"name":"Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 East Jingshi Road, Jinan 250103, China"},{"name":"Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, 28789 East Jingshi Road, Jinan 250103, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijie","family":"Xia","sequence":"additional","affiliation":[{"name":"Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 East Jingshi Road, Jinan 250103, China"},{"name":"Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, 28789 East Jingshi Road, Jinan 250103, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuanming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 East Jingshi Road, Jinan 250103, China"},{"name":"Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, 28789 East Jingshi Road, Jinan 250103, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 East Jingshi Road, Jinan 250103, China"},{"name":"Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, 28789 East Jingshi Road, Jinan 250103, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Molecular Engineering, School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kechun","family":"Liu","sequence":"additional","affiliation":[{"name":"Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 East Jingshi Road, Jinan 250103, China"},{"name":"Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, 28789 East Jingshi Road, Jinan 250103, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5572-2156","authenticated-orcid":false,"given":"Attila","family":"Sik","sequence":"additional","affiliation":[{"name":"University Research and Innovation Center, Obuda University, B\u00e9csi \u00fat 96B, H-1034 Budapest, Hungary"},{"name":"Institute of Physiology, Medical School, University of Pecs, H-7624 Pecs, Hungary"},{"name":"Institute of Clinical Sciences, Medical School, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5719-2187","authenticated-orcid":false,"given":"Rostyslav","family":"Stoika","sequence":"additional","affiliation":[{"name":"Department of Regulation of Cell Proliferation and Apoptosis, Institute of Cell Biology, National Academy of Sciences of Ukraine, 79005 Lviv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1525-0876","authenticated-orcid":false,"given":"Meng","family":"Jin","sequence":"additional","affiliation":[{"name":"Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 East Jingshi Road, Jinan 250103, China"},{"name":"Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, 28789 East Jingshi Road, Jinan 250103, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.neubiorev.2016.07.010","article-title":"Motor symptoms in Parkinson\u2019s disease: A unified framework","volume":"68","author":"Moustafa","year":"2016","journal-title":"Neurosci. 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