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Modulating microglial polarization from pro-inflammatory to anti-inflammatory phenotype is a promising therapeutic strategy for the treatment of cerebral ischemia. Polyphyllin I (PPI), a steroidal saponin, shows multiple bioactivities in various diseases, but the potential function of PPI in cerebral ischemia is not elucidated yet. In our study, the influence of PPI on cerebral ischemia\u2013reperfusion injury was evaluated. Mouse middle cerebral artery occlusion (MCAO) model and oxygen\u2013glucose deprivation and reoxygenation (OGD\/R) model were constructed to mimic cerebral ischemia\u2013reperfusion injury in vivo and in vitro. TTC staining, TUNEL staining, RT-qPCR, ELISA, flow cytometry, western blot, immunofluorescence, hanging wire test, rotarod test and foot-fault test, open-field test and Morris water maze test were performed in our study. We found that PPI alleviated cerebral ischemia\u2013reperfusion injury and neuroinflammation, and improved functional recovery of mice after MCAO. PPI modulated microglial polarization towards anti-inflammatory M2 phenotype in MCAO mice in vivo and post OGD\/R in vitro. Besides, PPI promoted autophagy via suppressing Akt\/mTOR signaling in microglia, while inhibition of autophagy abrogated the effect of PPI on M2 microglial polarization after OGD\/R. Furthermore, PPI facilitated autophagy-mediated ROS clearance to inhibit NLRP3 inflammasome activation in microglia, and NLRP3 inflammasome reactivation by nigericin abolished the effect of PPI on M2 microglia polarization. In conclusion, PPI alleviated post-stroke neuroinflammation and tissue damage via increasing autophagy-mediated M2 microglial polarization. Our data suggested that PPI had potential for ischemic stroke treatment.<\/jats:p>","DOI":"10.1186\/s10020-024-00828-5","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T09:01:49Z","timestamp":1715677309000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Polyphyllin I alleviates neuroinflammation after cerebral ischemia\u2013reperfusion injury via facilitating autophagy-mediated M2 microglial polarization"],"prefix":"10.1186","volume":"30","author":[{"given":"Chunyang","family":"Kang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuling","family":"Sang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingxi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Libo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6184-4869","authenticated-orcid":false,"given":"Xiaoyang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,14]]},"reference":[{"issue":"3","key":"828_CR1","doi-asserted-by":"publisher","first-page":"1742","DOI":"10.1073\/pnas.1914742117","volume":"117","author":"A Al Mamun","year":"2020","unstructured":"Al Mamun A, Chauhan A, Qi S, Ngwa C, Xu Y, Sharmeen R, Hazen AL, Li J, Aronowski JA, McCullough LD, et al. 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