{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:26:12Z","timestamp":1791919572553,"version":"4.3.4"},"reference-count":42,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82201719"],"award-info":[{"award-number":["82201719"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2023A1515140147"],"award-info":[{"award-number":["2023A1515140147"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Cytokine"],"published-print":{"date-parts":[[2025,12]]},"DOI":"10.1016\/j.cyto.2025.157036","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T01:12:23Z","timestamp":1758589943000},"page":"157036","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":3,"special_numbering":"C","title":["Neuregulin 4 attenuates osteoarthritis by decreasing macrophage M1 polarization through PI3K\/AKT signaling"],"prefix":"10.1016","volume":"196","author":[{"given":"Chao","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinjian","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengxin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puyi","family":"Sheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linli","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"issue":"7","key":"10.1016\/j.cyto.2025.157036_bb0005","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/j.joca.2023.03.003","article-title":"Osteoarthritis year in review 2022: genetics, genomics and epigenetics","volume":"31","author":"Kim","year":"2023","journal-title":"Osteoarthr. Cartil."},{"issue":"2","key":"10.1016\/j.cyto.2025.157036_bb0010","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.joca.2023.11.012","article-title":"Osteoarthritis year in review 2023: epidemiology & therapy","volume":"32","author":"Perruccio","year":"2024","journal-title":"Osteoarthr. Cartil."},{"issue":"1","key":"10.1016\/j.cyto.2025.157036_bb0015","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1097\/BOR.0000000000000353","article-title":"Role of low-grade inflammation in osteoarthritis","volume":"29","author":"Scanzello","year":"2017","journal-title":"Curr. Opin. Rheumatol."},{"issue":"10","key":"10.1016\/j.cyto.2025.157036_bb0020","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/nrrheum.2016.136","article-title":"Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis","volume":"12","author":"Robinson","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"issue":"10","key":"10.1016\/j.cyto.2025.157036_bb0025","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1136\/annrheumdis-2018-213450","article-title":"Synovial macrophage M1 polarisation exacerbates experimental osteoarthritis partially through R-spondin-2","volume":"77","author":"Zhang","year":"2018","journal-title":"Ann. Rheum. Dis."},{"key":"10.1016\/j.cyto.2025.157036_bb0030","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.biomaterials.2018.07.011","article-title":"Cartilage repair in degenerative osteoarthritis mediated by squid type II collagen via immunomodulating activation of M2 macrophages, inhibiting apoptosis and hypertrophy of chondrocytes","volume":"180","author":"Dai","year":"2018","journal-title":"Biomaterials"},{"key":"10.1016\/j.cyto.2025.157036_bb0035","doi-asserted-by":"crossref","DOI":"10.1016\/j.biomaterials.2021.120865","article-title":"Artificial M2 macrophages for disease-modifying osteoarthritis therapeutics","volume":"274","author":"Ma","year":"2021","journal-title":"Biomaterials"},{"issue":"30","key":"10.1016\/j.cyto.2025.157036_bb0040","doi-asserted-by":"crossref","DOI":"10.1002\/adma.202202715","article-title":"Reprogramming mitochondrial metabolism in synovial macrophages of early osteoarthritis by a camouflaged Meta-Defensome","volume":"34","author":"Zhang","year":"2022","journal-title":"Adv. Mater."},{"issue":"5","key":"10.1016\/j.cyto.2025.157036_bb0045","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/j.apsb.2019.01.015","article-title":"Kinsenoside attenuates osteoarthritis by repolarizing macrophages through inactivating NF-\u03baB\/MAPK signaling and protecting chondrocytes","volume":"9","author":"Zhou","year":"2019","journal-title":"Acta Pharm. Sin. B"},{"issue":"3","key":"10.1016\/j.cyto.2025.157036_bb0050","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1148\/radiol.212009","article-title":"MRI-based texture analysis of infrapatellar fat pad to predict knee osteoarthritis incidence","volume":"304","author":"Li","year":"2022","journal-title":"Radiology"},{"issue":"5","key":"10.1016\/j.cyto.2025.157036_bb0055","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.14336\/AD.2019.1116","article-title":"Infrapatellar fat pad and knee osteoarthritis","volume":"11","author":"Zeng","year":"2020","journal-title":"Aging Dis."},{"key":"10.1016\/j.cyto.2025.157036_bb0060","article-title":"Single-cell atlas of human infrapatellar fat pad and synovium implicates APOE signaling in osteoarthritis pathology","volume":"16(731):eadf4590","author":"Tang","year":"2024","journal-title":"Sci. Transl. Med."},{"issue":"6","key":"10.1016\/j.cyto.2025.157036_bb0065","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1136\/annrheumdis-2011-200688","article-title":"Cytokine production by infrapatellar fat pad can be stimulated by interleukin 1\u03b2 and inhibited by peroxisome proliferator activated receptor \u03b1 agonist","volume":"71","author":"Clockaerts","year":"2012","journal-title":"Ann. Rheum. Dis."},{"issue":"22","key":"10.1016\/j.cyto.2025.157036_bb0070","article-title":"Blockage of Osteopontin-integrin \u03b23 signaling in infrapatellar fat pad attenuates osteoarthritis in mice","volume":"10","author":"Dai","year":"2023","journal-title":"Adv Sci (Weinh)"},{"issue":"6","key":"10.1016\/j.cyto.2025.157036_bb0075","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/j.cmet.2024.05.005","article-title":"The browning and mobilization of subcutaneous white adipose tissue supports efficient skin repair","volume":"36","author":"Cai","year":"2024","journal-title":"Cell Metab."},{"issue":"1","key":"10.1016\/j.cyto.2025.157036_bb0080","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s00223-021-00897-2","article-title":"Neuregulin 4 attenuates osteoarthritis progression by inhibiting inflammation and apoptosis of chondrocytes in mice","volume":"110","author":"Shi","year":"2022","journal-title":"Calcif. Tissue Int."},{"issue":"12","key":"10.1016\/j.cyto.2025.157036_bb0085","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1038\/nm.3713","article-title":"The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis","volume":"20","author":"Wang","year":"2014","journal-title":"Nat. Med."},{"key":"10.1016\/j.cyto.2025.157036_bb0090","doi-asserted-by":"crossref","DOI":"10.1016\/j.bcp.2024.116327","article-title":"Adipocyte secreted NRG4 ameliorates age-associated metabolic dysfunction","volume":"225","author":"Chen","year":"2024","journal-title":"Biochem. Pharmacol."},{"issue":"10","key":"10.1016\/j.cyto.2025.157036_bb0095","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.2337\/db21-0064","article-title":"Mutations of NRG4 contribute to the pathogenesis of nonalcoholic fatty liver disease and related metabolic disorders","volume":"70","author":"Li","year":"2021","journal-title":"Diabetes"},{"issue":"11","key":"10.1016\/j.cyto.2025.157036_bb0100","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1038\/s42255-022-00671-0","article-title":"Brown adipose tissue-derived Nrg4 alleviates endothelial inflammation and atherosclerosis in male mice","volume":"4","author":"Shi","year":"2022","journal-title":"Nat. Metab."},{"issue":"6","key":"10.1016\/j.cyto.2025.157036_bb0105","doi-asserted-by":"crossref","first-page":"G990","DOI":"10.1152\/ajpgi.00296.2020","article-title":"NRG4-ErbB4 signaling represses proinflammatory macrophage activity","volume":"320","author":"Schumacher","year":"2021","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"issue":"2","key":"10.1016\/j.cyto.2025.157036_bb0110","doi-asserted-by":"crossref","DOI":"10.1038\/cddis.2017.42","article-title":"ErbB4 signaling stimulates pro-inflammatory macrophage apoptosis and limits colonic inflammation","volume":"8","author":"Schumacher","year":"2017","journal-title":"Cell Death Dis."},{"issue":"9","key":"10.1016\/j.cyto.2025.157036_bb0115","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/j.joca.2007.03.006","article-title":"The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129\/SvEv mouse","volume":"15","author":"Glasson","year":"2007","journal-title":"Osteoarthr. Cartil."},{"issue":"4","key":"10.1016\/j.cyto.2025.157036_bb0120","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1111\/j.1365-2559.2006.02508.x","article-title":"Synovitis score: discrimination between chronic low-grade and high-grade synovitis","volume":"49","author":"Krenn","year":"2006","journal-title":"Histopathology"},{"key":"10.1016\/j.cyto.2025.157036_bb0125","doi-asserted-by":"crossref","DOI":"10.1002\/0471142735.im1401s83","article-title":"The isolation and characterization of murine macrophages","author":"Zhang","year":"2008","journal-title":"Curr. Protoc. Immunol."},{"issue":"17","key":"10.1016\/j.cyto.2025.157036_bb0130","doi-asserted-by":"crossref","first-page":"2681","DOI":"10.1038\/sj.onc.1202631","article-title":"Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase","volume":"18","author":"Harari","year":"1999","journal-title":"Oncogene"},{"issue":"16","key":"10.1016\/j.cyto.2025.157036_bb0135","article-title":"Neuregulin4 acts on hypothalamic ErBb4 to excite oxytocin neurons and preserve metabolic homeostasis","volume":"10","author":"Zhang","year":"2023","journal-title":"Adv Sci (Weinh)"},{"issue":"2","key":"10.1016\/j.cyto.2025.157036_bb0140","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1002\/jcb.24362","article-title":"Vertical inhibition of the PI3K\/Akt\/mTOR pathway for the treatment of osteoarthritis","volume":"114","author":"Chen","year":"2013","journal-title":"J. Cell. Biochem."},{"issue":"4","key":"10.1016\/j.cyto.2025.157036_bb0145","doi-asserted-by":"crossref","first-page":"2735","DOI":"10.3892\/etm.2016.3642","article-title":"Shikonin inhibits inflammation and chondrocyte apoptosis by regulation of the PI3K\/Akt signaling pathway in a rat model of osteoarthritis","volume":"12","author":"Fu","year":"2016","journal-title":"Exp. Ther. Med."},{"issue":"7","key":"10.1016\/j.cyto.2025.157036_bb0150","doi-asserted-by":"crossref","first-page":"3073","DOI":"10.1016\/j.apsb.2022.02.010","article-title":"Targeting macrophagic SHP2 for ameliorating osteoarthritis via TLR signaling","volume":"12","author":"Sun","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"issue":"1","key":"10.1016\/j.cyto.2025.157036_bb0155","doi-asserted-by":"crossref","first-page":"2876","DOI":"10.1038\/s41467-019-10753-5","article-title":"The microRNAs miR-204 and miR-211 maintain joint homeostasis and protect against osteoarthritis progression","volume":"10","author":"Huang","year":"2019","journal-title":"Nat. Commun."},{"issue":"3","key":"10.1016\/j.cyto.2025.157036_bb0160","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1097\/JSA.0000000000000349","article-title":"Biological targets of multimolecular therapies in middle-age osteoarthritis","volume":"30","author":"Andia","year":"2022","journal-title":"Sports Med. Arthrosc. Rev."},{"issue":"5","key":"10.1016\/j.cyto.2025.157036_bb0165","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/j.joca.2019.12.007","article-title":"The role of macrophages in osteoarthritis and cartilage repair","volume":"28","author":"Wu","year":"2020","journal-title":"Osteoarthr. Cartil."},{"issue":"11","key":"10.1016\/j.cyto.2025.157036_bb0170","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/nrrheum.2010.159","article-title":"The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis","volume":"6","author":"Sellam","year":"2010","journal-title":"Nat. Rev. Rheumatol."},{"key":"10.1016\/j.cyto.2025.157036_bb0175","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejphar.2020.173090","article-title":"Macrophage M1\/M2 polarization","volume":"877","author":"Yunna","year":"2020","journal-title":"Eur. J. Pharmacol."},{"issue":"3","key":"10.1016\/j.cyto.2025.157036_bb0180","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1002\/art.27290","article-title":"The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive responses in osteoarthritis","volume":"62","author":"Bondeson","year":"2010","journal-title":"Arthritis Rheum."},{"issue":"1","key":"10.1016\/j.cyto.2025.157036_bb0185","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1186\/s13018-024-05052-9","article-title":"Research progress on macrophage polarization during osteoarthritis disease progression: a review","volume":"19","author":"Yin","year":"2024","journal-title":"J. Orthop. Surg. Res."},{"issue":"9","key":"10.1016\/j.cyto.2025.157036_bb0190","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1016\/j.cmet.2022.07.010","article-title":"Neuregulin 4 suppresses NASH-HCC development by restraining tumor-prone liver microenvironment","volume":"34","author":"Zhang","year":"2022","journal-title":"Cell Metab."},{"issue":"8","key":"10.1016\/j.cyto.2025.157036_bb0195","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/j.molmet.2017.03.016","article-title":"Nrg4 promotes fuel oxidation and a healthy adipokine profile to ameliorate diet-induced metabolic disorders","volume":"6","author":"Chen","year":"2017","journal-title":"Mol Metab"},{"issue":"4","key":"10.1016\/j.cyto.2025.157036_bb0200","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.joca.2015.11.014","article-title":"Synovitis and radiographic progression in non-erosive and erosive hand osteoarthritis: is erosive hand osteoarthritis a separate inflammatory phenotype?","volume":"24","author":"Haugen","year":"2016","journal-title":"Osteoarthr. Cartil."},{"key":"10.1016\/j.cyto.2025.157036_bb0205","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.cytogfr.2019.03.004","article-title":"Clinical implications of macrophage dysfunction in the development of osteoarthritis of the knee","volume":"46","author":"Xie","year":"2019","journal-title":"Cytokine Growth Factor Rev."},{"key":"10.1016\/j.cyto.2025.157036_bb0210","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.biopha.2017.10.130","article-title":"Aqueous extract of Codium fragile alleviates osteoarthritis through the MAPK\/NF-\u03baB pathways in IL-1\u03b2-induced rat primary chondrocytes and a rat osteoarthritis model","volume":"97","author":"Moon","year":"2018","journal-title":"Biomed. Pharmacother."}],"container-title":["Cytokine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1043466625001838?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1043466625001838?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T09:16:54Z","timestamp":1762593414000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1043466625001838"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":42,"alternative-id":["S1043466625001838"],"URL":"https:\/\/doi.org\/10.1016\/j.cyto.2025.157036","relation":{},"ISSN":["1043-4666"],"issn-type":[{"value":"1043-4666","type":"print"}],"subject":[],"published":{"date-parts":[[2025,12]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Neuregulin 4 attenuates osteoarthritis by decreasing macrophage M1 polarization through PI3K\/AKT signaling","name":"articletitle","label":"Article Title"},{"value":"Cytokine","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.cyto.2025.157036","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2025 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"157036"}}