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In this study, a chemical proteomic strategy is employed using the active compound procyanidin B3 (PB3) as a chemical probe to identify the therapeutic targets for IS. It is discovered that the Ras GTPase\u2010activating protein SH3 domain\u2010binding protein 1 (G3BP1) is a key target of PB3, which exerts a neuroprotective effect by inhibiting the degradation of stress granules and reducing apoptosis. Based on this finding, 14 PB3 derivatives are designed and synthesized, among which compound\n                    <jats:bold>6c<\/jats:bold>\n                    exhibited potent neuroprotective activity and favorable blood\u2010brain barrier permeability. This study not only establishes G3BP1 as a promising therapeutic target for IS but also highlights the potential of PB3 and its derivatives for the development of IS therapeutic agents.\n                  <\/jats:p>","DOI":"10.1002\/advs.202509781","type":"journal-article","created":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T05:35:16Z","timestamp":1758951316000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Procyanidin B3 and Its Derivatives Alleviate Neuronal Injury by Targeting G3BP1 for Ischemic Stroke Therapy"],"prefix":"10.1002","volume":"12","author":[{"given":"Heyanhao","family":"Zhang","sequence":"first","affiliation":[{"name":"Phenome Research Center of TCM Department of Traditional Chinese Medicine Shanghai Pudong Hospital Pharmacophenomics Laboratory Human Phenome Institute Fudan University Shanghai 201203 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