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Most studies regarding the therapeutic potential of neferine (Nef) on IS have focused on neuroprotective effect. However, whether Nef attenuates BBB disruption during IS is unclear. We here used mice underwent transient middle cerebral artery occlusion (tMCAO) in vivo and bEnd.3 cells exposed to oxygen\u2013glucose deprivation\/reoxygenation (OGD\/R) injury in vitro to simulate cerebral ischemia. We showed that Nef reduced neurobehavioral dysfunction and protected brain microvascular endothelial cells and BBB integrity. Molecular docking, short interfering (Si) RNA and plasmid transfection results showed us that PGC-1\u03b1 was the most binding affinity of biological activity protein for Nef. And verification experiments were showed that Nef upregulated PGC-1\u03b1 expression to reduce mitochondrial oxidative stress and promote TJ proteins expression, further improves the integrity of BBB in mice. Intriguingly, our study showed that neferine is a natural PGC-1\u03b1 activator and illustrated the mechanism of specific binding site. Furthermore, we have demonstrated Nef reduced mitochondria oxidative damage and ameliorates endothelial inflammation by inhibiting pyroptosis to improve BBB permeability through triggering a cascade reaction of PGC-1\u03b1 via regulation of PGC-1\u03b1\/NLRP3\/GSDMD signaling pathway to maintain the integrity of BBB in ischemia\/reperfusion injury.<\/jats:p>","DOI":"10.1038\/s41598-024-64815-w","type":"journal-article","created":{"date-parts":[[2024,6,23]],"date-time":"2024-06-23T11:02:24Z","timestamp":1719140544000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Neferine inhibits BMECs pyroptosis and maintains blood\u2013brain barrier integrity in ischemic stroke by triggering a cascade reaction of PGC-1\u03b1"],"prefix":"10.1038","volume":"14","author":[{"given":"Zi-jian","family":"Zheng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-zhi","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wu-yin-xiao","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng-tao","family":"You","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu-he","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun-ling","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun-rong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya-jun","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,6,23]]},"reference":[{"key":"64815_CR1","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.freeradbiomed.2019.11.005","volume":"146","author":"Z He","year":"2020","unstructured":"He, Z., Ning, N., Zhou, Q., Khoshnam, S. E. & Farzaneh, M. Mitochondria as a therapeutic target for ischemic stroke. Free Radic. Biol. Med. 146, 45\u201358. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2019.11.005 (2020).","journal-title":"Free Radic. Biol. Med."},{"key":"64815_CR2","doi-asserted-by":"publisher","DOI":"10.1007\/s10495-021-01661-5","author":"J Jia","year":"2021","unstructured":"Jia, J., Jin, H., Nan, D., Yu, W. & Huang, Y. New insights into targeting mitochondria in ischemic injury. Apoptosis https:\/\/doi.org\/10.1007\/s10495-021-01661-5 (2021).","journal-title":"Apoptosis"},{"key":"64815_CR3","doi-asserted-by":"publisher","DOI":"10.3390\/antiox12051075","author":"SO Abu","year":"2023","unstructured":"Abu, S. O., Arroum, T., Morris, S. & Busch, K. B. PGC-1\u03b1 Is a master regulator of mitochondrial lifecycle and ROS stress response. 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