{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T01:37:30Z","timestamp":1790213850453,"version":"4.1.0"},"reference-count":58,"publisher":"Walter de Gruyter GmbH","issue":"2","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec id=\"j_jtim-2026-0010_s_006\">\n                    <jats:title>Background and Objectives<\/jats:title>\n                    <jats:p>Ischemic stroke triggers pathological neuroinflammation primarily mediated by microglial activation. However, the epigenetic impact of lactate, a metabolite that accumulates during cerebral ischemia, on this process has not been comprehensively investigated. This study aimed to determine whether lactate influences microglial polarization through histone lactylation during prolonged cerebral ischemia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_jtim-2026-0010_s_007\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>In vitro<\/jats:italic>\n                      models using lactate-treated BV-2 microglia and\n                      <jats:italic>in vivo<\/jats:italic>\n                      models of transient middle cerebral artery occlusion (MCAO) mice were established. Analyses were conducted at 4 to 12 h post-occlusion. Our comprehensive analysis included H3K9la-targeted CUT&amp; Tag sequencing, Nrf2 promoter-specific ChIP-qPCR, flow cytometry for polarization markers, cytokine enzyme-linked immunosorbent assays (ELISAs), and neuronal viability assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_jtim-2026-0010_s_008\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Under ischemic conditions, lactate markedly increased H3K9 lactylation, with selective enrichment at Nrf2 promoters. This epigenetic modification resulted in a phenotypic shift toward anti-inflammatory M2 states in microglia, both\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      . Mechanistically, H3K9la activated the Nrf2\/HO-1 pathway, effectively suppressing nuclear factor kappa-light-chain-enhancer of activated B cells (NF-\u03baB) signaling and significantly reducing pro-inflammatory cytokine secretion. Importantly, conditioned medium derived from lactate-treated microglia mitigated the neurotoxic efects induced by microglia to some extent.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_jtim-2026-0010_s_009\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our findings suggest that lactate confers neuroprotection\n                      <jats:italic>via<\/jats:italic>\n                      epigenetic activation of Nrf2\n                      <jats:italic>via<\/jats:italic>\n                      H3K9la, thereby polarizing microglia towards inflammation-resolving states. This finding uncovers a novel metabolic-epigenetic target for therapeutic intervention in ischemic stroke.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1515\/jtim-2026-0010","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T12:58:48Z","timestamp":1774529928000},"page":"276-293","source":"Crossref","is-referenced-by-count":3,"title":["Lactate modulates microglial M2 polarization\n                    <i>via<\/i>\n                    H3K9 lactylation in ischemic stroke"],"prefix":"10.1515","volume":"14","author":[{"given":"Bingwei","family":"Li","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, First Hospital of Jilin University , Changchun , Jilin Province , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8947-1172","authenticated-orcid":false,"given":"Kan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, First Hospital of Jilin University , Changchun , Jilin Province , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2329-7946","authenticated-orcid":false,"given":"Jinlu","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, First Hospital of Jilin University , Changchun , Jilin Province , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"2026042612202587247_j_jtim-2026-0010_ref_001","doi-asserted-by":"crossref","unstructured":"GBD 2016 Neurology Collaborators. 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