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Cerebral ischemia-reperfusion injury (CIRI) and neuroinflammation induced by CIRI represents a challenge for clinical therapy of ischemic stroke. Epigallocatechin-3-gallate (EGCG), the predominant catechin in green tea, is known to mitigate ischemic stroke and inflammation, while its role in regulating neuroinflammation post-recanalization remains unclear. This study aimed to explore the effect and mechanism of EGCG on the regulation of CIRI. The CIRI in vivo model was established by middle cerebral artery occlusion\/reperfusion (MCAO\/R) in rats and EGCG was administered via intracerebroventricular injection before MCAO\/R. The neurological scores, infarct volume, neuronal injury, and microglial biomarkers were evaluated. BV2 cells subjected to oxygen\u2013glucose deprivation\/reoxygenation (OGD\/R) were used to establish an in vitro CIRI model. After pretreatment with EGCG and\/or ML385, OGD\/R, cell viability, microglial biomarkers, pro-inflammatory and anti-inflammatory factors, and transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) were detected. Different conditioned media collected from BV2 cells were used for culturing the neuronal mimic cell line SH-SY5Y. EGCG administration in vivo significantly improved neurological deficits, infarct volume, and neuronal damage. Moreover, pretreatment with EGCG significantly increased BV2 cells viability and anti-inflammatory factors, and reduced toxicity and ferroptosis in SH-SY5Y cells. Furthermore, the upregulation of M2 markers was consistent with in vivo experiments. However, this protective effect was abolished by ML385, an Nrf2 inhibitor. EGCG upregulated Nrf2 and HO-1 protein expression, thus promoting microglial polarization toward the M2 phenotype. EGCG has a protective effect on CIRI by promoting the polarization of microglia toward the M2 phenotype via the Nrf2\/HO-1 pathway to inhibit ferroptosis of neuron, which may provide a novel target for ischemic stroke treatment.<\/jats:p>","DOI":"10.1038\/s41598-026-60227-0","type":"journal-article","created":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T02:35:07Z","timestamp":1782614107000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Epigallocatechin-3-gallate mitigates cerebral ischemia-reperfusion injury by promoting microglia toward M2 phenotype via Nrf2\/HO-1 pathway"],"prefix":"10.1038","volume":"16","author":[{"given":"Yan","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanfeng","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizhu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,28]]},"reference":[{"key":"60227_CR1","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1001\/jama.2024.0572","volume":"331","author":"A Sarraj","year":"2024","unstructured":"Sarraj, A. et al. 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