{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T12:59:36Z","timestamp":1785157176929,"version":"3.55.0"},"reference-count":58,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81771250"],"award-info":[{"award-number":["81771250"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2024J011004"],"award-info":[{"award-number":["2024J011004"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Astrocyte reactivity critically shapes neuroinflammatory outcomes after ischemic stroke, yet the upstream regulators governing astrocyte state transitions remain incompletely defined. Here, we identify the immunoproteasome subunit low molecular weight protein 2 (LMP2) as an important modulator of astrocyte functional remodeling following cerebral ischemia\/reperfusion (I\/R). Using global and astrocyte\u2010specific knockout models, we demonstrate that LMP2 deficiency markedly reduces infarct volume, attenuates neuroinflammation, and improves neurological and cognitive outcomes. Mechanistically, LMP2 coordinately modulates inflammatory and reparative signaling networks by promoting nuclear factor kappa\u2010B (NF\u2010\u03baB)\u2010dependent inflammatory activation while constraining transforming growth factor\u2010\u03b21(TGF\u2010\u03b21)\/SMAD family member 3 (Smad3)\u2010associated reparative responses, thereby biasing astrocyte reactive states toward more inflammatory and maladaptive programs along the inflammatory\u2010reparative continuum. Conversely, LMP2 inhibition promoted more adaptive and neuroprotective astrocyte\u2010associated programs, enhanced neurotrophic support, and limited apoptosis under ischemic stress. Integrative transcriptomic and single\u2010cell analyses further revealed that astrocyte responses exist along a continuum of functional states, with LMP2 influencing the distribution of astrocyte states rather than acting as a binary switch. Collectively, these findings uncover a previously unrecognized immunoproteasome\u2010astrocyte regulatory axis involved in neuroinflammatory remodeling and highlight LMP2 as a promising target for precision modulation of post\u2010ischemic brain injury.<\/jats:p>","DOI":"10.1002\/advs.202523902","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T12:03:41Z","timestamp":1785153821000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Astrocytic LMP2 Coordinates NF\u2010\u03baB and TGF\u2010\u03b21\/Smad3 Signaling to Drive Neuroinflammation after Cerebral Ischemia\/Reperfusion"],"prefix":"10.1002","author":[{"given":"Yanguang","family":"Mao","sequence":"first","affiliation":[{"name":"Department of Neurology Shengli Clinical Medical College of Fujian Medical University Fuzhou University Affiliated Provincial Hospital  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rulan","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Neurology Shengli Clinical Medical College of Fujian Medical University Fuzhou University Affiliated Provincial Hospital  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zejing","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neurology Shengli Clinical Medical College of Fujian Medical University Fuzhou University Affiliated Provincial Hospital  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiying","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurology Shengli Clinical Medical College of Fujian Medical University Fuzhou University Affiliated Provincial Hospital  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuexian","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology Shengli Clinical Medical College of Fujian Medical University Fuzhou University Affiliated Provincial Hospital  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghe","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Neurology Shengli Clinical Medical College of Fujian Medical University Fuzhou University Affiliated Provincial Hospital  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology Shengli Clinical Medical College of Fujian Medical University Fuzhou University Affiliated Provincial Hospital  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7364-5414","authenticated-orcid":false,"given":"Xingyong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology Shengli Clinical Medical College of Fujian Medical University Fuzhou University Affiliated Provincial Hospital  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1474\u20104422(18)30499\u2010x"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2012.98"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pcad.2017.04.005"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2015.144"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/neup.12928"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adi7828"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593\u2010021\u201000905\u20106"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2021.105080"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2025.01.002"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2025.5490"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.11.018"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108829"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c00416"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2021.102167"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1001517"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1978"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2014.586"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10571\u2010012\u20109854\u2010y"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420\u2010025\u201002698\u20100"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.2741\/4027"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41401\u2010024\u201001267\u2010y"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0056187"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.05.029"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.str.20.1.84"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1097\/wnr.0000000000001715"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202412667"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2018.04.009"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967\u2010023\u201004071\u20100"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967\u2010023\u201004071\u20100"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471\u20102202\u201014\u201056"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1612930114"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nlz079"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582\u2010023\u201000822\u20101"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010023\u201001628\u20109"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2022.105456"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010023\u201006935\u20103"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.26918"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcz028"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.982786"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awt083"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010017\u201009715\u2010y"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201303543"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2020.07.004"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.96375"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2025.1575022"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1177\/17448069221140532"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awn109"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.4103\/1673\u20105374.389630"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0092\u20108674(94)90482\u20100"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a022061"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2025.08.004"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.4103\/1673\u20105374.377588"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1097\u20102765(00)00134\u20109"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1093\/abbs\/gmp018"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.str.0000126891.93919.4e"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201708089"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jstrokecerebrovasdis.2016.08.027"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.4103\/1673\u20105374.295344"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202523902","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.202523902","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202523902","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T12:03:43Z","timestamp":1785153823000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202523902"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":58,"alternative-id":["10.1002\/advs.202523902"],"URL":"https:\/\/doi.org\/10.1002\/advs.202523902","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,27]]},"assertion":[{"value":"2025-11-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e23902"}}