{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:08:23Z","timestamp":1789517303460,"version":"build-2803163510"},"reference-count":78,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T00:00:00Z","timestamp":1739318400000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"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":["82302794"],"award-info":[{"award-number":["82302794"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2023M741469"],"award-info":[{"award-number":["2023M741469"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Spinal cord injury (SCI) is a severe condition leading to significant disability and high mortality. The role of the secreted phosphoprotein 1 (SPP1) signaling pathway in SCI, which is quickly activated after injury, is critical for intercellular communication but remains poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>This study aimed to explore the function and regulatory mechanisms of the SPP1 signaling pathway in SCI and investigate its potential as a therapeutic target for improving functional recovery after injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>\n                      Single\u2010cell RNA sequencing (scRNA\u2010seq) was employed to identify ligands and receptors of the SPP1 signaling pathway, particularly in microglia\/macrophages. Recombinant SPP1 (rSPP1) was used in\u00a0vitro and in\u00a0vivo to assess its effects on neuronal maturation, mitochondrial energy in axons, and functional recovery after SCI. Pseudotime analysis was conducted to examine the role of\n                      <jats:italic>Spp1<\/jats:italic>\n                      in microglial activation and proliferation. DNA\u2010pulldown and in\u00a0vitro experiments were performed to investigate the upstream regulatory proteins of\n                      <jats:italic>Spp1<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The SPP1 signaling pathway is primarily localized in microglia after SCI, with rSPP1 promoting neuronal maturation and enhancing mitochondrial function in axons. Injection of rSPP1 into the injured spinal cord resulted in significant improvement in functional recovery. Pseudotime analysis indicated that\n                      <jats:italic>Spp1<\/jats:italic>\n                      is involved in the activation and proliferation of microglia. Histone H4 lysine 12 lactylation (H4K12la) was found to promote the transcription of\n                      <jats:italic>Spp1<\/jats:italic>\n                      in reprogrammed microglia postinjury.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Our findings reveal a novel regulatory mechanism involving\n                      <jats:italic>Spp1<\/jats:italic>\n                      in SCI, particularly its role in microglial activation, mitochondrial function, and glycolytic reprogramming. This new insight provides a deeper understanding of its contribution to the injury response.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study uncovers a previously unreported mechanism of\n                      <jats:italic>Spp1<\/jats:italic>\n                      in SCI, offering a potential therapeutic target for SCI.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/cns.70232","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T23:30:17Z","timestamp":1739403017000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["<scp>H4K12<\/scp>\n                    Lactylation Activated\u2010\n                    <i>Spp1<\/i>\n                    in Reprogrammed Microglia Improves Functional Recovery After Spinal Cord Injury"],"prefix":"10.1111","volume":"31","author":[{"given":"Xiaokun","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Orthopedics The First Affiliated Hospital of Nanjing Medical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geliang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of First Clinical Medical College of Nanjing Medical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjun","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The First Affiliated Hospital of Nanjing Medical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wu","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The First Affiliated Hospital of Nanjing Medical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The First Affiliated Hospital of Nanjing Medical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haofan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The First Affiliated Hospital of Nanjing Medical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dishui","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The First Affiliated Hospital of Nanjing Medical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjun","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The Fourth Affiliated Hospital of Soochow University  Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1145-0463","authenticated-orcid":false,"given":"Zheng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Emergency and Critical Care Medicine Department The First Affiliated Hospital of Nanjing Medical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,12]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.18"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2015.6250"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.wneu.2018.02.033"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-00885-4"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-40513-5"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxac060"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awl094"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.02.017"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12868-017-0348-1"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1089\/089771503321532879"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1292\/jvms.66.1307"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-004-0926-z"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-003-0775-1"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/BRS.0000000000004954"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.reth.2023.11.004"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2019.02.029"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1678-1"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109820"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-021-02308-z"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-020-0267-9"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2022.02.013"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2021.101932"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-1571-8"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.12.009"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3125"},{"key":"e_1_2_11_27_1","first-page":"fj201800548","article-title":"GPCR Kinase 2\u2010Interacting Protein\u20101 Protects Against Ischemia\u2010Reperfusion Injury of the Spinal Cord by Modulating ASK1\/JNK\/p38 Signaling","volume":"32","author":"Chen J.","year":"2018","journal-title":"FASEB Journal"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2015.12.004"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2024.03.025"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2023.04.011"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-022-00710-w"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2009.03159.x"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jir185"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-022-00904-x"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2001.01702.x"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.27571"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/all.13646"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-020-0376-2"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00017810"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni1327"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.05.008"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200425672"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.13081"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI12980"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.10170"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.15641"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2008.08.001"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.2002.17.8.1486"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1093\/qjmed\/95.1.3"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1097\/WNR.0b013e328355380e"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.01.008"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.2174\/156720507779939869"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2005.02.020"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2007.03.016"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8090980"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-015-9480-z"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.acthis.2012.08.004"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2019.10.043"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.238717"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/emm.2017.241"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.31083\/j.jin2202033"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.24411"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-020-0072-x"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2021.08.011"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2021.04.079"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-020-00289-0"},{"key":"e_1_2_11_67_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12975-019-00728-5"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-018-1279-1"},{"key":"e_1_2_11_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.10.020"},{"key":"e_1_2_11_70_1","doi-asserted-by":"publisher","DOI":"10.14336\/AD.2023.0505"},{"key":"e_1_2_11_71_1","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.783"},{"key":"e_1_2_11_72_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05788-0"},{"key":"e_1_2_11_73_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-31797-0"},{"key":"e_1_2_11_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.05.003"},{"key":"e_1_2_11_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2022.04.001"},{"key":"e_1_2_11_76_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15267-z"},{"key":"e_1_2_11_77_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23760"},{"key":"e_1_2_11_78_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2016.140"},{"key":"e_1_2_11_79_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2019.06.006"}],"container-title":["CNS Neuroscience &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cns.70232","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cns.70232","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cns.70232","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T13:49:13Z","timestamp":1777902553000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cns.70232"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2]]},"references-count":78,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,2]]}},"alternative-id":["10.1111\/cns.70232"],"URL":"https:\/\/doi.org\/10.1111\/cns.70232","archive":["Portico"],"relation":{},"ISSN":["1755-5930","1755-5949"],"issn-type":[{"value":"1755-5930","type":"print"},{"value":"1755-5949","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2]]},"assertion":[{"value":"2024-05-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70232"}}