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Cordycepin is a natural derivative of the nucleoside adenosine that displays potent antioxidant, antitumor, anti\u2010inflammatory, and neuroprotective properties. However, the mechanism of the neuroprotective effect of cordycepin toward A\u03b2\u2010induced neurotoxicity, as well as underlying mechanisms, is still unclear. In this study, we found that cordycepin conferred neuroprotection to catecholaminergic PC12 neuronal cell cultures exposed to A\u03b2<jats:sub>1\u201342<\/jats:sub>\u2010insult by reducing the production of reactive oxygen species, restoring the mitochondrial membrane potential, and inhibiting apoptosis. Cordycepin stimulated the phosphorylation of extracellular signal\u2010regulated kinase (ERK) and cyclic AMP\u2010responsive element\u2010binding protein (CREB) in a time\u2010 and concentration\u2010dependent manner. Inhibition of the ERK pathway reduced the neuroprotective effect of cordycepin. Similar results were obtained with hippocampal HT22 neuronal cell cultures. Cumulatively, these findings suggest that cordycepin\u2010induced neuroprotection toward A\u03b2<jats:sub>1\u201342<\/jats:sub> neurotoxic insult may involve activation of the ERK\/CREB pathway. This study expands our knowledge of the neuroprotective function of cordycepin and suggests that it holds promise as a natural lead compound for drug development in AD.<\/jats:p>","DOI":"10.1002\/ibra.12192","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T05:39:28Z","timestamp":1739252368000},"page":"84-97","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Cordycepin mediates neuroprotection against apoptosis via ERK\/CREB signaling activation in A\u03b2<sub>1\u201342<\/sub>\u2010induced neuronal cell models"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8015-6992","authenticated-orcid":false,"given":"Wenshu","family":"Zhou","sequence":"first","affiliation":[{"name":"Faculty of Health Sciences, and Zhuhai UM Science &amp; Technology Research Institute University of Macau Macau SAR China"},{"name":"State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine Kunming University of Science and Technology Kunming China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Research in Chinese Medicine University of Macau Macao SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yige","family":"Tan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine Kunming University of Science and Technology Kunming China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Lazarovici","sequence":"additional","affiliation":[{"name":"School of Pharmacy Institute for Drug Research, Faculty of Medicine The Hebrew University of Jerusalem Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Wen","sequence":"additional","affiliation":[{"name":"Zhongshan Key Laboratory of Zebrafish\u2010based Drug Innovation, ZebraPeutics (Zhongshan) Ltd. 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