{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:31:56Z","timestamp":1791361916397,"version":"4.3.1"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T00:00:00Z","timestamp":1762732800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T00:00:00Z","timestamp":1762732800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Acta Pharmacol Sin"],"published-print":{"date-parts":[[2026,3]]},"DOI":"10.1038\/s41401-025-01689-2","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T09:50:21Z","timestamp":1762768221000},"page":"576-592","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Resibufogenin ameliorates cerebral ischemia-reperfusion injury by modulating microglial redox homeostasis via Keap1-Nrf2-TFR1\/ARE axis"],"prefix":"10.1038","volume":"47","author":[{"given":"Yao","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-qing","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-bo","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo-qiang","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shou-jiao","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-ge","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"key":"1689_CR1","doi-asserted-by":"publisher","first-page":"e347","DOI":"10.1161\/CIR.0000000000001209","volume":"149","author":"SS Martin","year":"2024","unstructured":"Martin SS, Aday AW, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, et al. 2024 heart disease and stroke statistics: a report of US and global data from the American heart association. Circulation. 2024;149:e347\u2013913.","journal-title":"Circulation"},{"key":"1689_CR2","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1016\/S0140-6736(24)01410-7","volume":"404","author":"TN Nguyen","year":"2024","unstructured":"Nguyen TN, Abdalkader M, Fischer U, Qiu ZM, Nagel S, Chen HS, et al. Endovascular management of acute stroke. Lancet. 2024;404:1265\u201378.","journal-title":"Lancet"},{"key":"1689_CR3","doi-asserted-by":"publisher","first-page":"185","DOI":"10.7861\/clinmed.2022-0554","volume":"23","author":"PS Dhillon","year":"2023","unstructured":"Dhillon PS, White P, Goyal M, van Zwam WH, Lenthall R. Perfusion imaging in acute ischaemic stroke-the beginning of the end?. Clin Med. 2023;23:185\u20136.","journal-title":"Clin Med"},{"key":"1689_CR4","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1097\/00003246-198807000-00015","volume":"16","author":"GS Krause","year":"1988","unstructured":"Krause GS, White BC, Aust SD, Nayini NR, Kumar K. Brain cell death following ischemia and reperfusion: a proposed biochemical sequence. Crit Care Med. 1988;16:714\u201326.","journal-title":"Crit Care Med"},{"key":"1689_CR5","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1111\/j.1527-3466.2008.00041.x","volume":"26","author":"T Watanabe","year":"2008","unstructured":"Watanabe T, Tahara M, Todo S. The novel antioxidant edaravone: from bench to bedside. Cardiovasc Ther. 2008;26:101\u201314.","journal-title":"Cardiovasc Ther"},{"key":"1689_CR6","doi-asserted-by":"publisher","first-page":"3555","DOI":"10.3390\/cells10123555","volume":"10","author":"SR Var","year":"2021","unstructured":"Var SR, Shetty AV, Grande AW, Low WC, Cheeran MC. Microglia and macrophages in neuroprotection, neurogenesis, and emerging therapies for stroke. Cells. 2021;10:3555.","journal-title":"Cells"},{"key":"1689_CR7","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1007\/s11064-025-04406-x","volume":"50","author":"SX Lin","year":"2025","unstructured":"Lin SX, Shi CL, Zhao L, Xian L, Yang WW, Wang ZY, et al. The ubiquitination and degradation of SH2B3 mediated by MEF2A\/WWP2 axis restores microglial homeostasis to alleviate cerebral microvascular endothelial cell injury in ischemic stroke. Neurochem Res. 2025;50:170.","journal-title":"Neurochem Res"},{"key":"1689_CR8","doi-asserted-by":"publisher","first-page":"2201","DOI":"10.3390\/antiox11112201","volume":"11","author":"QY Wu","year":"2022","unstructured":"Wu QY, Zou CY. Microglial dysfunction in neurodegenerative diseases via RIPK1 and ROS. Antioxidants. 2022;11:2201.","journal-title":"Antioxidants"},{"key":"1689_CR9","first-page":"2749","volume":"60","author":"JR Pan","year":"2023","unstructured":"Pan JR, Peng JL, Li XP, Wang HX, Rong XM, Peng Y. Transmission of NLRP3-IL-1\u03b2 signals in cerebral ischemia and reperfusion injury: from microglia to adjacent neuron and endothelial cells via IL-1\u03b2\/IL-1R1\/TRAF6. Mol Neurobiol. 2023;60:2749\u201366.","journal-title":"Mol Neurobiol"},{"key":"1689_CR10","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2023.110201","volume":"119","author":"KW Guo","year":"2023","unstructured":"Guo KW, Shang YX, Wang Z, Yu L, Chen JL, Zhu BF, et al. BRG1 alleviates microglial activation by promoting the Keap1-Nrf2\/HO-1 signaling pathway and minimizing oxidative damage in cerebral ischemia-reperfusion. Int Immunopharmacol. 2023;119:110201.","journal-title":"Int Immunopharmacol"},{"key":"1689_CR11","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2022.101756","volume":"82","author":"M George","year":"2022","unstructured":"George M, Tharakan M, Culberson J, Reddy AP, Reddy PH. Role of Nrf2 in aging, Alzheimer\u2019s and other neurodegenerative diseases. Ageing Res Rev. 2022;82:101756.","journal-title":"Ageing Res Rev"},{"key":"1689_CR12","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.abb.2016.08.005","volume":"617","author":"AT Dinkova-Kostova","year":"2017","unstructured":"Dinkova-Kostova AT, Kostov RV, Canning P. Keap1, the cysteine-based mammalian intracellular sensor for electrophiles and oxidants. Arch Biochem Biophys. 2017;617:84\u201393.","journal-title":"Arch Biochem Biophys"},{"key":"1689_CR13","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1152\/physrev.00023.2017","volume":"98","author":"M Yamamoto","year":"2018","unstructured":"Yamamoto M, Kensler TW, Motohashi H. The Keap1-Nrf2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol Rev. 2018;98:1169\u2013203.","journal-title":"Physiol Rev"},{"key":"1689_CR14","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102852","volume":"66","author":"YY Sun","year":"2023","unstructured":"Sun YY, Zhu HJ, Zhao RY, Zhou SY, Wang MQ, Yang Y, et al. Remote ischemic conditioning attenuates oxidative stress and inflammation via the Nrf2\/HO-1 pathway in MCAO mice. Redox Biol. 2023;66:102852.","journal-title":"Redox Biol"},{"key":"1689_CR15","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.jare.2020.07.011","volume":"34","author":"H Xu","year":"2020","unstructured":"Xu H, Shen JG, Xiao JB, Chen F, Wang MF. Neuroprotective effect of cajaninstilbene acid against cerebral ischemia and reperfusion damages by activating AMPK\/Nrf2 pathway. J Adv Res. 2020;34:199\u2013210.","journal-title":"J Adv Res"},{"key":"1689_CR16","doi-asserted-by":"publisher","first-page":"4490","DOI":"10.3390\/ijms23094490","volume":"23","author":"CA Porras","year":"2022","unstructured":"Porras CA, Rouault TA. Iron homeostasis in the CNS: an overview of the pathological consequences of iron metabolism disruption. Int J Mol Sci. 2022;23:4490.","journal-title":"Int J Mol Sci"},{"key":"1689_CR17","doi-asserted-by":"publisher","first-page":"1672","DOI":"10.1111\/brv.12521","volume":"94","author":"ZM Qian","year":"2019","unstructured":"Qian ZM, Ke Y. Brain iron transport. Biol Rev Camb Philos Soc. 2019;94:1672\u201384.","journal-title":"Biol Rev Camb Philos Soc"},{"key":"1689_CR18","doi-asserted-by":"publisher","first-page":"4591","DOI":"10.3390\/ijms22094591","volume":"22","author":"AS Vogt","year":"2021","unstructured":"Vogt AS, Arsiwala T, Mohsen M, Vogel M, Manolova V, Bachmann MF. On iron metabolism and its regulation. Int J Mol Sci. 2021;22:4591.","journal-title":"Int J Mol Sci"},{"key":"1689_CR19","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.3390\/brainsci13101367","volume":"13","author":"HY Tian","year":"2023","unstructured":"Tian HY, Huang BY, Nie HF, Chen XY, Zhou Y, Yang T, et al. The interplay between mitochondrial dysfunction and ferroptosis during ischemia-associated central nervous system diseases. Brain Sci. 2023;13:1367.","journal-title":"Brain Sci"},{"key":"1689_CR20","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/j.freeradbiomed.2022.10.314","volume":"193","author":"P Han","year":"2022","unstructured":"Han P, Wang X, Zhou TQ, Cheng JM, Wang CN, Sun F, et al. Inhibition of ferroptosis attenuates oligospermia in male Nrf2 knockout mice. Free Radic Biol Med. 2022;193:421\u20139.","journal-title":"Free Radic Biol Med"},{"key":"1689_CR21","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.3324\/haematol.2009.020123","volume":"95","author":"S Marro","year":"2010","unstructured":"Marro S, Chiabrando D, Messana E, Stolte J, Turco E, Tolosano E, et al. Heme controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE\/ARE sequence motif at position \u22127007 of the FPN1 promoter. Haematologica. 2010;95:1261\u20138.","journal-title":"Haematologica"},{"key":"1689_CR22","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102987","volume":"69","author":"X Luo","year":"2024","unstructured":"Luo X, Wang YH, Zhu XX, Chen YW, Xu BY, Bai XX, et al. MCL attenuates atherosclerosis by suppressing macrophage ferroptosis via targeting Keap1\/Nrf2 interaction. Redox Biol. 2024;69:102987.","journal-title":"Redox Biol"},{"key":"1689_CR23","doi-asserted-by":"publisher","first-page":"1982","DOI":"10.1038\/s41418-022-00990-5","volume":"29","author":"YL Wang","year":"2022","unstructured":"Wang YL, Yan S, Liu XM, Deng F, Wang PC, Yang LY, et al. PRMT4 promotes ferroptosis to aggravate doxorubicin-induced cardiomyopathy via inhibition of the Nrf2\/GPX4 pathway. Cell Death Differ. 2022;29:1982\u201395.","journal-title":"Cell Death Differ"},{"key":"1689_CR24","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1038\/s41593-022-01221-3","volume":"26","author":"SK Ryan","year":"2023","unstructured":"Ryan SK, Zelic M, Han YN, Teeple E, Chen LM, Sadeghi M, et al. Microglia ferroptosis is regulated by SEC24B and contributes to neurodegeneration. Nat Neurosci. 2023;26:12\u201326.","journal-title":"Nat Neurosci"},{"key":"1689_CR25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2024.176553","volume":"972","author":"WL Duan","year":"2024","unstructured":"Duan WL, Ma YP, Wang XJ, Ma CS, Han B, Sheng ZM, et al. N6022 attenuates cerebral ischemia\/reperfusion injury-induced microglia ferroptosis by promoting Nrf2 nuclear translocation and inhibiting the GSNOR\/GSTP1 axis. Eur J Pharmacol. 2024;972:176553.","journal-title":"Eur J Pharmacol"},{"key":"1689_CR26","doi-asserted-by":"publisher","first-page":"70","DOI":"10.3109\/10641955.2010.525275","volume":"31","author":"MN Uddin","year":"2012","unstructured":"Uddin MN, Agunanne EE, Horvat D, Puschett JB. Resibufogenin administration prevents oxidative stress in a rat model of human preeclampsia. Hypertens Pregnancy. 2012;31:70\u20138.","journal-title":"Hypertens Pregnancy"},{"key":"1689_CR27","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2022.109312","volume":"113","author":"Y Gao","year":"2022","unstructured":"Gao Y, Xu ZL, Li XM, Liu ZZ, Li WJ, Kang Y, et al. Resibufogenin, one of bufadienolides in toad venom, suppresses LPS-induced inflammation via inhibiting NF-\u03baB and AP-1 pathways. Int Immunopharmacol. 2022;113:109312.","journal-title":"Int Immunopharmacol"},{"key":"1689_CR28","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-018-1580-x","volume":"16","author":"QR Han","year":"2018","unstructured":"Han QR, Ma Y, Wang H, Dai Y, Chen CH, Liu YW, et al. Resibufogenin suppresses colorectal cancer growth and metastasis through RIP3-mediated necroptosis. J Transl Med. 2018;16:201.","journal-title":"J Transl Med"},{"key":"1689_CR29","doi-asserted-by":"publisher","unstructured":"Chen XY, Chen YJ, Zhai CG, Du WY, Chen ZJ, Wang J, et al. Resibufogenin protects against atherosclerosis in ApoE-\/- mice through blocking NLRP3 inflammasome assembly. J Adv Res. 2025 https:\/\/doi.org\/10.1016\/j.jare.2025.04.029.","DOI":"10.1016\/j.jare.2025.04.029"},{"key":"1689_CR30","first-page":"169","volume":"6","author":"JT Xie","year":"1985","unstructured":"Xie JT, Belic N, McCullough J, Singer DH. Effects of resibufogenin on the action potential of myocardial fibers of the dog and guinea pig. Zhongguo Yao Li Xue Bao. 1985;6:169\u201371.","journal-title":"Zhongguo Yao Li Xue Bao"},{"key":"1689_CR31","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1161\/01.STR.17.3.472","volume":"17","author":"JB Bederson","year":"1986","unstructured":"Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke. 1986;17:472\u20136.","journal-title":"Stroke"},{"key":"1689_CR32","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/s41401-023-01177-5","volume":"45","author":"XN Li","year":"2024","unstructured":"Li XN, Shang NY, Kang YY, Sheng N, Lan JQ, Tang JS, et al. Caffeic acid alleviates cerebral ischemic injury in rats by resisting ferroptosis via Nrf2 signaling pathway. Acta Pharmacol Sin. 2024;45:248\u201367.","journal-title":"Acta Pharmacol Sin"},{"key":"1689_CR33","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2020.172944","volume":"872","author":"PW Luan","year":"2020","unstructured":"Luan PW, Xu JZ, Ding XY, Cui QF, Jiang LX, Xu YL, et al. Neuroprotective effect of salvianolate on cerebral ischaemia-reperfusion injury in rats by inhibiting the caspase-3 signal pathway. Eur J Pharmacol. 2020;872:172944.","journal-title":"Eur J Pharmacol"},{"key":"1689_CR34","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.jneumeth.2010.03.026","volume":"189","author":"H Shiotsuki","year":"2010","unstructured":"Shiotsuki H, Yoshimi K, Shimo Y, Funayama M, Takamatsu Y, Ikeda K, et al. A rotarod test for evaluation of motor skill learning. J Neurosci Methods. 2010;189:180\u20135.","journal-title":"J Neurosci Methods"},{"key":"1689_CR35","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2024.103324","volume":"76","author":"SJ Peng","year":"2024","unstructured":"Peng SJ, Chen Y, Wang R, Zhang JG. Z-ligustilide provides a neuroprotective effect by regulating the phenotypic polarization of microglia via activating Nrf2-TrxR axis in the Parkinson\u2019s disease mouse model. Redox Biol. 2024;76:103324.","journal-title":"Redox Biol"},{"key":"1689_CR36","doi-asserted-by":"publisher","first-page":"1158","DOI":"10.1111\/1744-7917.12741","volume":"27","author":"H Yu","year":"2020","unstructured":"Yu H, Li ZQ, Ou-Yang YY, Huang GH. Identification of four caspase genes from Spodoptera exigua (Lepidoptera: Noctuidae) and their regulations toward different apoptotic stimulations. Insect Sci. 2020;27:1158\u201372.","journal-title":"Insect Sci"},{"key":"1689_CR37","doi-asserted-by":"publisher","first-page":"5242","DOI":"10.1021\/acs.jmedchem.5b00410","volume":"58","author":"SJ Peng","year":"2015","unstructured":"Peng SJ, Zhang BX, Meng XK, Yao J, Fang JG. Synthesis of piperlongumine analogues and discovery of nuclear factor erythroid 2-related factor 2 (Nrf2) activators as potential neuroprotective agents. J Med Chem. 2015;58:5242\u201355.","journal-title":"J Med Chem"},{"key":"1689_CR38","doi-asserted-by":"publisher","first-page":"3164","DOI":"10.3390\/ijms24043164","volume":"24","author":"Y Chen","year":"2023","unstructured":"Chen Y, Zhang R, Yang LQ, Zhang P, Wang FY, Lin GQ, et al. Eltrombopag inhibits metastasis in breast carcinoma by targeting HuR protein. Int J Mol Sci. 2023;24:3164.","journal-title":"Int J Mol Sci"},{"key":"1689_CR39","doi-asserted-by":"publisher","first-page":"5805","DOI":"10.1007\/s12035-023-03433-5","volume":"60","author":"G Sahoo","year":"2023","unstructured":"Sahoo G, Samal D, Khandayataray P, Murthy MK. A review on caspases: key regulators of biological activities and apoptosis. Mol Neurobiol. 2023;60:5805\u201337.","journal-title":"Mol Neurobiol"},{"key":"1689_CR40","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2025.109888","volume":"140","author":"A Catapano","year":"2025","unstructured":"Catapano A, Cimmino F, Petrella L, Pizzella A, D\u2019Angelo M, Ambrosio K, et al. Iron metabolism and ferroptosis in health and diseases: the crucial role of mitochondria in metabolically active tissues. J Nutr Biochem. 2025;140:109888.","journal-title":"J Nutr Biochem"},{"key":"1689_CR41","doi-asserted-by":"publisher","first-page":"1756","DOI":"10.1089\/ars.2017.7176","volume":"29","author":"MJ Kerins","year":"2018","unstructured":"Kerins MJ, Ooi A. The roles of Nrf2 in modulating cellular iron homeostasis. Antioxid Redox Signal. 2018;29:1756\u201373.","journal-title":"Antioxid Redox Signal"},{"key":"1689_CR42","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s12017-018-08523-5","volume":"21","author":"G Bahn","year":"2019","unstructured":"Bahn G, Jo DG. Therapeutic approaches to Alzheimer\u2019s disease through modulation of Nrf2. Neuromolecular Med. 2019;21:1\u201311.","journal-title":"Neuromolecular Med"},{"key":"1689_CR43","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-023-02991-8","volume":"21","author":"S Chen","year":"2024","unstructured":"Chen S, Pan JR, Gong Z, Wu ML, Zhang XN, Chen HS, et al. Hypochlorous acid derived from microglial myeloperoxidase could mediate high-mobility group box 1 release from neurons to amplify brain damage in cerebral ischemia-reperfusion injury. J Neuroinflammation. 2024;21:70.","journal-title":"J Neuroinflammation"},{"key":"1689_CR44","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1002\/glia.440070114","volume":"7","author":"PL McGeer","year":"1993","unstructured":"McGeer PL, Kawamata T, Walker DG, Akiyama H, Tooyama I, McGeer EG. Microglia in degenerative neurological disease. Glia. 1993;7:84\u201392.","journal-title":"Glia"},{"key":"1689_CR45","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2022.154112","volume":"102","author":"QW Hu","year":"2022","unstructured":"Hu QW, Zuo TR, Deng L, Chen S, Yu W, Liu SW, et al. \u03b2-Caryophyllene suppresses ferroptosis induced by cerebral ischemia reperfusion via activation of the Nrf2\/HO-1 signaling pathway in MCAO\/R rats. Phytomedicine. 2022;102:154112.","journal-title":"Phytomedicine"},{"key":"1689_CR46","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102706","volume":"62","author":"KN Shi","year":"2023","unstructured":"Shi KN, Li PB, Su HX, Gao J, Li HH. MK-886 protects against cardiac ischaemia\/reperfusion injury by activating proteasome-Keap1-Nrf2 signalling. Redox Biol. 2023;62:102706.","journal-title":"Redox Biol"},{"key":"1689_CR47","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.3390\/nu10111605","volume":"10","author":"W Rungratanawanich","year":"2018","unstructured":"Rungratanawanich W, Memo M, Uberti D. Redox homeostasis and natural dietary compounds: focusing on antioxidants of rice (Oryza sativa L.). Nutrients. 2018;10:1605.","journal-title":"Nutrients"},{"key":"1689_CR48","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1177\/0748233709102209","volume":"25","author":"HQ Zhang","year":"2009","unstructured":"Zhang HQ, Forman HJ. Signaling pathways involved in phase II gene induction by \u03b1,\u03b2-unsaturated aldehydes. Toxicol Ind Health. 2009;25:269\u201378.","journal-title":"Toxicol Ind Health"},{"key":"1689_CR49","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.ijpharm.2010.04.005","volume":"393","author":"F Li","year":"2010","unstructured":"Li F, Weng Y, Wang LH, He HB, Yang JY, Tang X. The efficacy and safety of bufadienolides-loaded nanostructured lipid carriers. Int J Pharm. 2010;393:204\u201312.","journal-title":"Int J Pharm."},{"key":"1689_CR50","doi-asserted-by":"publisher","first-page":"266","DOI":"10.3390\/ijms21010266","volume":"21","author":"G Schiera","year":"2019","unstructured":"Schiera G, Liegro CMD, Liegro ID. Cell-to-cell communication in learning and memory: from neuro- and glio-transmission to information exchange mediated by extracellular vesicles. Int J Mol Sci. 2019;21:266.","journal-title":"Int J Mol Sci"},{"key":"1689_CR51","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.jare.2024.01.006","volume":"66","author":"Y Hu","year":"2024","unstructured":"Hu Y, Tao WW. Current perspectives on microglia-neuron communication in the central nervous system: direct and indirect modes of interaction. J Adv Res. 2024;66:251\u201365.","journal-title":"J Adv Res"},{"key":"1689_CR52","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2020.105103","volume":"160","author":"Y Zhao","year":"2020","unstructured":"Zhao Y, Yang JH, Li C, Zhou GY, Wan HF, Ding ZS, et al. Role of the neurovascular unit in the process of cerebral ischemic injury. Pharmacol Res. 2020;160:105103.","journal-title":"Pharmacol Res"},{"key":"1689_CR53","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1007\/s12264-019-00388-3","volume":"35","author":"C Qin","year":"2019","unstructured":"Qin C, Zhou LQ, Ma XT, Hu ZW, Yang S, Chen M, et al. Dual functions of microglia in ischemic stroke. Neurosci Bull. 2019;35:921\u201333.","journal-title":"Neurosci Bull"},{"key":"1689_CR54","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1038\/aps.2012.178","volume":"34","author":"YC Huang","year":"2012","unstructured":"Huang YC, Feng ZP. The good and bad of microglia\/macrophages: new hope in stroke therapeutics. Acta Pharmacol Sin. 2012;34:6\u20137.","journal-title":"Acta Pharmacol Sin"},{"key":"1689_CR55","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-017-0963-x","volume":"14","author":"S Chen","year":"2017","unstructured":"Chen S, Dong ZP, Cheng M, Zhao YQ, Wang MY, Sai N, et al. Homocysteine exaggerates microglia activation and neuroinflammation through microglia localized STAT3 overactivation following ischemic stroke. J Neuroinflammation. 2017;14:187.","journal-title":"J Neuroinflammation"},{"key":"1689_CR56","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2019.101107","volume":"23","author":"M Dodson","year":"2019","unstructured":"Dodson M, Castro-Portuguez R, Zhang DD. Nrf2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol. 2019;23:101107.","journal-title":"Redox Biol"},{"key":"1689_CR57","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurot.2024.e00444","volume":"21","author":"ML Sun","year":"2024","unstructured":"Sun ML, Chen JM, Liu F, Li P, Lu JD, Ge SH, et al. Butylphthalide inhibits ferroptosis and ameliorates cerebral ischaemia-reperfusion injury in rats by activating the Nrf2\/HO-1 signalling pathway. Neurotherapeutics. 2024;21:e00444.","journal-title":"Neurotherapeutics"},{"key":"1689_CR58","doi-asserted-by":"publisher","first-page":"6626","DOI":"10.7150\/thno.77243","volume":"12","author":"J Zhang","year":"2022","unstructured":"Zhang J, Pan WQ, Zhang Y, Tan MY, Yin YF, Li YM, et al. Comprehensive overview of Nrf2-related epigenetic regulations involved in ischemia-reperfusion injury. Theranostics. 2022;12:6626\u201345.","journal-title":"Theranostics"},{"key":"1689_CR59","doi-asserted-by":"publisher","first-page":"1516","DOI":"10.1016\/j.bcp.2006.07.030","volume":"72","author":"EH Kim","year":"2006","unstructured":"Kim EH, Surh YJ. 15-deoxy-delta12,14-prostaglandin J2 as a potential endogenous regulator of redox-sensitive transcription factors. Biochem Pharmacol. 2006;72:1516\u201328.","journal-title":"Biochem Pharmacol"},{"key":"1689_CR60","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2020.118982","volume":"284","author":"TI Adelusi","year":"2021","unstructured":"Adelusi TI, Du L, Chowdhury A, Gu XK, Lu Q, Yin XX. Signaling pathways and proteins targeted by antidiabetic chalcones. Life Sci. 2021;284:118982.","journal-title":"Life Sci."},{"key":"1689_CR61","doi-asserted-by":"publisher","first-page":"7986","DOI":"10.1021\/acs.jmedchem.9b01865","volume":"63","author":"Y Zhang","year":"2020","unstructured":"Zhang Y, Shi ZY, Zhou YJ, Xiao Q, Wang HY, Peng Y. Emerging substrate proteins of Kelch-like ECH associated protein 1 (Keap1) and potential challenges for the development of small-molecule inhibitors of the Keap1-nuclear factor Erythroid 2-related factor 2 (Nrf2) protein-protein interaction. J Med Chem. 2020;63:7986\u20138002.","journal-title":"J Med Chem."},{"key":"1689_CR62","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2020.113820","volume":"173","author":"JW Shin","year":"2020","unstructured":"Shin JW, Chun KS, Kim DH, Kim SJ, Kim SH, Cho NC, et al. Curcumin induces stabilization of Nrf2 protein through Keap1 cysteine modification. Biochem Pharmacol. 2020;173:113820.","journal-title":"Biochem Pharmacol"}],"container-title":["Acta Pharmacologica Sinica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41401-025-01689-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41401-025-01689-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41401-025-01689-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T19:03:26Z","timestamp":1771959806000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41401-025-01689-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,10]]},"references-count":62,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["1689"],"URL":"https:\/\/doi.org\/10.1038\/s41401-025-01689-2","relation":{},"ISSN":["1671-4083","1745-7254"],"issn-type":[{"value":"1671-4083","type":"print"},{"value":"1745-7254","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,10]]},"assertion":[{"value":"19 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All procedures involving animals complied with the ethical standards of the institution where the studies were conducted. No research involving human participants was conducted.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}