{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:19:27Z","timestamp":1790727567760,"version":"4.1.0"},"reference-count":43,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T00:00:00Z","timestamp":1741910400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key R&amp;D Program of China","award":["2022YFE0104000"],"award-info":[{"award-number":["2022YFE0104000"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Gastrodin (gas) has been shown to promote neuroprotection and reverse Alzheimer\u2019s disease (AD) pathology. However, its high effective dose limits its potential in treating AD. In this study, a bioassay system using PC12 cells and the nerve growth factor (NGF)-mimic effect was employed to investigate the structure\u2013activity relationship of gas derivatives. Among the synthesized compounds, GAD037 demonstrated the highest NGF-mimic activity, surpassing gas. Additionally, GAD037 exhibited significant neuroprotective effects, reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels, thereby improving the survival of PC12 cells under oxidative stress. It also protected cells from A\u03b2-induced toxicity. Target protein identification and mechanistic studies revealed that insulin receptor (INSR) and alpha-actinin-4 (ACTN4) are potential targets of GAD037, confirmed through specific inhibitors, small interfering RNA (siRNA) analysis, a cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS). Moreover, the phosphatidylinositol 3-kinase (PI3K)\/protein kinase B (Akt) and rat sarcoma (Ras)\/protooncogene serine\u2013threonine protein kinase (Raf)\/mitogen-activated protein kinase (MEK)\/extracellular signal-regulated kinase (ERK) signaling pathways were found to be involved in the NGF-mimic activity of GAD037. In conclusion, GAD037 exhibits superior NGF-mimic and neuroprotective activities compared to gas, suggesting its potential as a lead compound for anti-AD applications.<\/jats:p>","DOI":"10.3390\/antiox14030344","type":"journal-article","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T13:07:51Z","timestamp":1741957671000},"page":"344","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Novel Gastrodin Derivative with Neuroprotection Promotes NGF-Mimic Activity by Targeting INSR and ACTN4 to Activate PI3K\/Akt Signaling Pathway in PC12 Cells"],"prefix":"10.3390","volume":"14","author":[{"given":"Jiayuan","family":"Zeng","sequence":"first","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianxia","family":"Mo","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Muroi","sequence":"additional","affiliation":[{"name":"Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako 351-0198, Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3606-4925","authenticated-orcid":false,"given":"Hiroyuki","family":"Osada","sequence":"additional","affiliation":[{"name":"Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako 351-0198, Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6595-2836","authenticated-orcid":false,"given":"Lan","family":"Xiang","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Qi","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s disease","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"eadd6260","DOI":"10.1126\/science.add6260","article-title":"Pharmacological modulation of septins restores calcium homeostasis and is neuroprotective in models of Alzheimer\u2019s disease","volume":"384","author":"Princen","year":"2024","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s13024-024-00702-2","article-title":"Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid \u03b2 aggregates in vivo in a mouse model of Alzheimer\u2019s disease","volume":"19","author":"Kharitonova","year":"2024","journal-title":"Mol. 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