{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:44:27Z","timestamp":1792788267333,"version":"4.5.0"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T00:00:00Z","timestamp":1792627200000},"content-version":"vor","delay-in-days":87,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"name":"National Natural Science Foundation of China","award":["82571811"],"award-info":[{"award-number":["82571811"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Nanobiotechnol"],"DOI":"10.1186\/s12951-026-04832-1","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T06:33:05Z","timestamp":1785133985000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spermidine, a chondrocyte apoptotic metabolite, delays osteoarthritis by regulating macrophage M2c polarization"],"prefix":"10.1186","volume":"24","author":[{"given":"Jiajia","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbiao","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangnan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianan","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinling","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhibin","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"4832_CR1","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1038\/s41572-025-00594-6","volume":"11","author":"S Tang","year":"2025","unstructured":"Tang S, Zhang C, Oo WM, Fu K, Risberg MA, Bierma-Zeinstra SM, et al. Osteoarthritis Nat Rev Dis Primers. 2025;11:10.","journal-title":"Osteoarthritis Nat Rev Dis Primers"},{"issue":"Suppl 120","key":"4832_CR2","first-page":"3","volume":"37","author":"GA Hawker","year":"2019","unstructured":"Hawker GA. Osteoarthritis is a serious disease. Clin Exp Rheumatol. 2019;37(Suppl 120):3\u20136.","journal-title":"Clin Exp Rheumatol"},{"key":"4832_CR3","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/j.joca.2021.04.020","volume":"30","author":"KD Allen","year":"2022","unstructured":"Allen KD, Thoma LM, Golightly YM. Epidemiology of osteoarthritis. Osteoarthritis Cartilage. 2022;30:184\u201395.","journal-title":"Osteoarthritis Cartilage"},{"key":"4832_CR4","unstructured":"Global, regional, and national burden of osteoarthritis, 1990\u20132020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Rheumatol. 2023;5:e508\u2013508e522."},{"key":"4832_CR5","doi-asserted-by":"publisher","first-page":"1697","DOI":"10.1002\/art.34453","volume":"64","author":"RF Loeser","year":"2012","unstructured":"Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 2012;64:1697\u2013707.","journal-title":"Arthritis Rheum"},{"key":"4832_CR6","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1016\/j.cell.2011.10.033","volume":"147","author":"Y Fuchs","year":"2011","unstructured":"Fuchs Y, Steller H. Programmed cell death in animal development and disease. Cell. 2011;147:742\u201358.","journal-title":"Cell"},{"key":"4832_CR7","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1146\/annurev-pathmechdis-051022-014433","volume":"19","author":"N Kayagaki","year":"2024","unstructured":"Kayagaki N, Webster JD, Newton K. Control of cell death in health and disease. Annu Rev Pathol. 2024;19:157\u201380.","journal-title":"Annu Rev Pathol"},{"key":"4832_CR8","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1146\/annurev-pathmechdis-051222-115023","volume":"20","author":"A Moyer","year":"2025","unstructured":"Moyer A, Tanaka K, Cheng EH. Apoptosis in cancer biology and therapy. Annu Rev Pathol. 2025;20:303\u201328.","journal-title":"Annu Rev Pathol"},{"key":"4832_CR9","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1111\/j.1756-185X.2011.01618.x","volume":"14","author":"Z Zamli","year":"2011","unstructured":"Zamli Z, Sharif M. Chondrocyte apoptosis: a cause or consequence of osteoarthritis. Int J Rheum Dis. 2011;14:159\u201366.","journal-title":"Int J Rheum Dis"},{"key":"4832_CR10","doi-asserted-by":"publisher","first-page":"1347126","DOI":"10.3389\/fcell.2024.1347126","volume":"12","author":"YT Lee","year":"2024","unstructured":"Lee YT, MohdYunus MH, Yazid MD, Ugusman A. Unraveling the path to osteoarthritis management: targeting chondrocyte apoptosis for therapeutic intervention. Front Cell Dev Biol. 2024;12:1347126.","journal-title":"Front Cell Dev Biol"},{"key":"4832_CR11","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1136\/annrheumdis-2014-205894","volume":"75","author":"I Atukorala","year":"2016","unstructured":"Atukorala I, Kwoh CK, Guermazi A, Roemer FW, Boudreau RM, Hannon MJ, et al. Synovitis in knee osteoarthritis: a precursor of disease. Ann Rheum Dis. 2016;75:390\u20135.","journal-title":"Ann Rheum Dis"},{"key":"4832_CR12","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1016\/j.joca.2019.12.007","volume":"28","author":"CL Wu","year":"2020","unstructured":"Wu CL, Harasymowicz NS, Klimak MA, Collins KH, Guilak F. The role of macrophages in osteoarthritis and cartilage repair. Osteoarthritis Cartilage. 2020;28:544\u201354.","journal-title":"Osteoarthritis Cartilage"},{"key":"4832_CR13","doi-asserted-by":"publisher","first-page":"1524","DOI":"10.1136\/annrheumdis-2018-213450","volume":"77","author":"H Zhang","year":"2018","unstructured":"Zhang H, Lin C, Zeng C, Wang Z, Wang H, Lu J, et al. Synovial macrophage M1 polarisation exacerbates experimental osteoarthritis partially through R-spondin-2. Ann Rheum Dis. 2018;77:1524\u201334.","journal-title":"Ann Rheum Dis"},{"key":"4832_CR14","doi-asserted-by":"publisher","first-page":"2921","DOI":"10.2147\/DDDT.S295224","volume":"15","author":"WM Oo","year":"2021","unstructured":"Oo WM, Little C, Duong V, Hunter DJ. The development of disease-modifying therapies for osteoarthritis (DMOADs): the evidence to date. Drug Des Devel Ther. 2021;15:2921\u201345.","journal-title":"Drug Des Devel Ther"},{"key":"4832_CR15","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1016\/j.joca.2014.11.010","volume":"23","author":"N Holzer","year":"2015","unstructured":"Holzer N, Salvo D, Marijnissen AC, Vincken KL, Ahmad AC, Serra E, et al. Radiographic evaluation of posttraumatic osteoarthritis of the ankle: the Kellgren-Lawrence scale is reliable and correlates with clinical symptoms. Osteoarthritis Cartilage. 2015;23:363\u20139.","journal-title":"Osteoarthritis Cartilage"},{"key":"4832_CR16","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1016\/j.joca.2007.03.006","volume":"15","author":"SS Glasson","year":"2007","unstructured":"Glasson SS, Blanchet TJ, Morris EA. The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129\/SvEv mouse. Osteoarthritis Cartilage. 2007;15:1061\u20139.","journal-title":"Osteoarthritis Cartilage"},{"issue":"Suppl 3","key":"4832_CR17","doi-asserted-by":"publisher","first-page":"S17","DOI":"10.1016\/j.joca.2010.05.025","volume":"18","author":"SS Glasson","year":"2010","unstructured":"Glasson SS, Chambers MG, Van Den Berg WB, Little CB. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the mouse. Osteoarthritis Cartilage. 2010;18(Suppl 3):S17-23.","journal-title":"Osteoarthritis Cartilage"},{"key":"4832_CR18","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1038\/nprot.2008.95","volume":"3","author":"M Gosset","year":"2008","unstructured":"Gosset M, Berenbaum F, Thirion S, Jacques C. Primary culture and phenotyping of murine chondrocytes. Nat Protoc. 2008;3:1253\u201360.","journal-title":"Nat Protoc"},{"key":"4832_CR19","doi-asserted-by":"publisher","DOI":"10.1186\/s11658-024-00614-5","volume":"29","author":"J Lu","year":"2024","unstructured":"Lu J, Shi X, Fu Q, Han Y, Zhu L, Zhou Z, et al. New mechanistic understanding of osteoclast differentiation and bone resorption mediated by P2X7 receptors and PI3K-Akt-GSK3\u03b2 signaling. Cell Mol Biol Lett. 2024;29:100.","journal-title":"Cell Mol Biol Lett"},{"key":"4832_CR20","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1038\/s41586-022-05041-0","volume":"609","author":"B Niemann","year":"2022","unstructured":"Niemann B, Haufs-Brusberg S, Puetz L, Feickert M, Jaeckstein MY, Hoffmann A, et al. Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine. Nature. 2022;609:361\u20138.","journal-title":"Nature"},{"key":"4832_CR21","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1016\/j.immuni.2024.03.021","volume":"57","author":"J Xiao","year":"2024","unstructured":"Xiao J, Wang S, Chen L, Ding X, Dang Y, Han M, et al. 25-Hydroxycholesterol regulates lysosome AMP kinase activation and metabolic reprogramming to educate immunosuppressive macrophages. Immunity. 2024;57:1087-104.e7.","journal-title":"Immunity"},{"key":"4832_CR22","doi-asserted-by":"publisher","first-page":"26035","DOI":"10.3390\/ijms161125943","volume":"16","author":"HS Hwang","year":"2015","unstructured":"Hwang HS, Kim HA. Chondrocyte apoptosis in the pathogenesis of osteoarthritis. Int J Mol Sci. 2015;16:26035\u201354.","journal-title":"Int J Mol Sci"},{"key":"4832_CR23","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1172\/JCI59643","volume":"122","author":"A Sica","year":"2012","unstructured":"Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122:787\u201395.","journal-title":"J Clin Invest"},{"key":"4832_CR24","doi-asserted-by":"publisher","first-page":"614","DOI":"10.3389\/fimmu.2014.00614","volume":"5","author":"N Wang","year":"2014","unstructured":"Wang N, Liang H, Zen K. Molecular mechanisms that influence the macrophage m1\u2013m2 polarization balance. Front Immunol. 2014;5:614.","journal-title":"Front Immunol"},{"key":"4832_CR25","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1002\/path.2792","volume":"223","author":"CD Gregory","year":"2011","unstructured":"Gregory CD, Pound JD. Cell death in the neighbourhood: direct microenvironmental effects of apoptosis in normal and neoplastic tissues. J Pathol. 2011;223:177\u201394.","journal-title":"J Pathol"},{"key":"4832_CR26","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1038\/s41586-020-2121-3","volume":"580","author":"CB Medina","year":"2020","unstructured":"Medina CB, Mehrotra P, Arandjelovic S, Perry J, Guo Y, Morioka S, et al. Metabolites released from apoptotic cells act as tissue messengers. Nature. 2020;580:130\u20135.","journal-title":"Nature"},{"key":"4832_CR27","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202410503","volume":"21","author":"Y Wang","year":"2025","unstructured":"Wang Y, Liu C, Pang J, Li Z, Zhang J, Dong L. The extra-tumoral vaccine effects of apoptotic bodies in the advancement of cancer treatment. Small. 2025;21:e2410503.","journal-title":"Small"},{"key":"4832_CR28","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1158\/1078-0432.CCR-24-4275","volume":"32","author":"Q Yu","year":"2026","unstructured":"Yu Q, Geng M, Lu Y, Zhang X, Tong S, Wang Y, et al. Spermidine secreted by apoptotic cells enhances chemotherapy resistance by modulating \u03b2-catenin activity in osteosarcoma. Clin Cancer Res. 2026;32:390\u2013404.","journal-title":"Clin Cancer Res"},{"key":"4832_CR29","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1186\/s12951-024-02820-x","volume":"22","author":"Y Qu","year":"2024","unstructured":"Qu Y, Meng B, Cai S, Yang B, He Y, Fu C, et al. Apoptotic metabolites ameliorate bone aging phenotypes via TCOF1\/FLVCR1-mediated mitochondrial homeostasis. J Nanobiotechnology. 2024;22:549.","journal-title":"J Nanobiotechnology"},{"key":"4832_CR30","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1080\/15548627.2018.1530929","volume":"15","author":"F Madeo","year":"2019","unstructured":"Madeo F, Bauer MA, Carmona-Gutierrez D, Kroemer G. Spermidine: a physiological autophagy inducer acting as an anti-aging vitamin in humans. Autophagy. 2019;15:165\u20138.","journal-title":"Autophagy"},{"key":"4832_CR31","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1016\/j.tcb.2023.08.002","volume":"34","author":"K Chamoto","year":"2024","unstructured":"Chamoto K, Zhang B, Tajima M, Honjo T, Fagarasan S. Spermidine - an old molecule with a new age-defying immune function. Trends Cell Biol. 2024;34:363\u201370.","journal-title":"Trends Cell Biol"},{"key":"4832_CR32","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-2710-y","volume":"11","author":"Z Chen","year":"2020","unstructured":"Chen Z, Lin CX, Song B, Li CC, Qiu JX, Li SX, et al. Spermidine activates RIP1 deubiquitination to inhibit TNF-\u03b1-induced NF-\u03baB\/p65 signaling pathway in osteoarthritis. Cell Death Dis. 2020;11:503.","journal-title":"Cell Death Dis"},{"key":"4832_CR33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s12276-018-0149-3","volume":"50","author":"PK Sacitharan","year":"2018","unstructured":"Sacitharan PK, Lwin S, Gharios GB, Edwards JR. Spermidine restores dysregulated autophagy and polyamine synthesis in aged and osteoarthritic chondrocytes via EP300. Exp Mol Med. 2018;50:1\u201310.","journal-title":"Exp Mol Med"},{"key":"4832_CR34","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1038\/nature23275","volume":"548","author":"CS Zhang","year":"2017","unstructured":"Zhang CS, Hawley SA, Zong Y, Li M, Wang Z, Gray A, et al. Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature. 2017;548:112\u20136.","journal-title":"Nature"},{"key":"4832_CR35","doi-asserted-by":"publisher","first-page":"1566","DOI":"10.1093\/rheumatology\/kew207","volume":"55","author":"W Zhang","year":"2016","unstructured":"Zhang W, Sun G, Aitken D, Likhodii S, Liu M, Martin G, et al. Lysophosphatidylcholines to phosphatidylcholines ratio predicts advanced knee osteoarthritis. Rheumatology (Oxford). 2016;55:1566\u201374.","journal-title":"Rheumatology (Oxford)"},{"key":"4832_CR36","doi-asserted-by":"publisher","first-page":"1479","DOI":"10.1016\/j.joca.2016.03.011","volume":"24","author":"RF Loeser","year":"2016","unstructured":"Loeser RF, Pathmasiri W, Sumner SJ, McRitchie S, Beavers D, Saxena P, et al. Association of urinary metabolites with radiographic progression of knee osteoarthritis in overweight and obese adults: an exploratory study. Osteoarthritis Cartilage. 2016;24:1479\u201386.","journal-title":"Osteoarthritis Cartilage"}],"container-title":["Journal of Nanobiotechnology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12951-026-04832-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12951-026-04832-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12951-026-04832-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T23:45:58Z","timestamp":1792626358000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12951-026-04832-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["4832"],"URL":"https:\/\/doi.org\/10.1186\/s12951-026-04832-1","relation":{},"ISSN":["1477-3155"],"issn-type":[{"value":"1477-3155","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,27]]},"assertion":[{"value":"9 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The study involving human samples was approved by the Ethics Committee of Navy Medical University (Shanghai, China, Approval No.240064). All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of Shanghai Fourth People\u2019s Hospital, Tongji University (protocol No. TJBH16525402).","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All the authors have agreed to publish this manuscript.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"977"}}