{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T14:59:13Z","timestamp":1792681153465,"version":"4.5.0"},"reference-count":57,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T00:00:00Z","timestamp":1725408000000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Pineal Research"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Recent evidence indicates that the damaged regions in osteoarthritis are accompanied by the accumulation of iron ions. Ferroptosis, as an iron\u2010dependent form of cell death, holds significant implications in osteoarthritis. Melatonin, a natural product with strong scavenging abilities against reactive oxygen species and lipid peroxidation, plays a crucial role in the treatment of osteoarthritis. This study aims to demonstrate the existence of ferroptosis in osteoarthritis and explore the specific mechanism of melatonin in suppressing ferroptosis and alleviating osteoarthritis. Our findings reveal that melatonin reverses inflammation\u2010induced oxidative stress and lipid peroxidation\u00a0while promoting the expression of extracellular matrix components in chondrocytes, safeguarding the cells. Our research has revealed that NADPH oxidase 4 (NOX4) serves as a crucial molecule in the ferroptosis process of osteoarthritis. Specifically, NOX4 is located on mitochondria in chondrocytes, which can induce disorders in mitochondrial energy metabolism and dysfunction, thereby intensifying oxidative stress and lipid peroxidation. LC\u2010MS analysis further uncovered that GRP78 is a downstream binding protein of NOX4. NOX4 induces ferroptosis by weakening GRP78's protective effect on GPX4 and reducing its expression. Melatonin can inhibit the upregulation of NOX4 on mitochondria and mitigate mitochondrial dysfunction, effectively suppressing ferroptosis and alleviating osteoarthritis. This suggests that melatonin therapy represents a promising new approach for the treatment of osteoarthritis.<\/jats:p>","DOI":"10.1111\/jpi.12992","type":"journal-article","created":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T03:21:18Z","timestamp":1725420078000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Melatonin Alleviates Osteoarthritis by Regulating NADPH Oxidase 4\u2013Induced Ferroptosis and Mitigating Mitochondrial Dysfunction"],"prefix":"10.1111","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5972-4754","authenticated-orcid":false,"given":"Qi","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Orthopedics Shanghai Pudong Hospital, Fudan University Pudong Medical Center  Shanghai Pudong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beijie","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Shanghai Pudong Hospital, Fudan University Pudong Medical Center  Shanghai Pudong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Shanghai Pudong Hospital, Fudan University Pudong Medical Center  Shanghai Pudong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihao","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Shanghai Pudong Hospital, Fudan University Pudong Medical Center  Shanghai Pudong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dejian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Shanghai Pudong Hospital, Fudan University Pudong Medical Center  Shanghai Pudong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinhua","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Shanghai Pudong Hospital, Fudan University Pudong Medical Center  Shanghai Pudong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengqing","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Shanghai Pudong Hospital, Fudan University Pudong Medical Center  Shanghai Pudong China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,9,4]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/geront\/gnw002"},{"issue":"9","key":"e_1_2_11_3_1","first-page":"646","article-title":"Burden of Major Musculoskeletal Conditions","volume":"81","author":"Woolf A. D.","year":"2003","journal-title":"Bulletin of the World Health Organization"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000000985"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.berh.2014.08.002"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.01.007"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.725568"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-014-1579-2"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.00528"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12514"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2017.11.001"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.11.048"},{"issue":"1","key":"e_1_2_11_13_1","first-page":"30","article-title":"Synovial Iron Deposition in Osteoarthritis and Rheumatoid Arthritis","volume":"7","author":"Ogilvie\u2010Harris D. J.","year":"1980","journal-title":"The Journal of Rheumatology"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1426-6"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.042"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.3109\/10715762.2013.808743"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1089\/cmb.2017.0096"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12448"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2023.110359"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-013-9454-x"},{"key":"e_1_2_11_21_1","doi-asserted-by":"crossref","unstructured":"G. M.Morris R.Huey andA. J.Olson \u201cUsing AutoDock for Ligand\u2013Receptor Docking \u201d\u00a0Current Protocols in Bioinformatics(2008): 1\u201340 https:\/\/doi.org\/10.1002\/0471250953.bi0814s24.","DOI":"10.1002\/0471250953.bi0814s24"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.6.2195"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/9.1.37"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2023.08.012"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2021.101947"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10060890"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2022.102474"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1703856114"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.h1225"},{"key":"e_1_2_11_30_1","doi-asserted-by":"crossref","DOI":"10.1136\/bmj-2022-070753","article-title":"Paracetamol Use in Adults","volume":"383","author":"Caparrotta T. M.","year":"2023","journal-title":"BMJ"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2019.06.011"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.781389"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1159\/000355720"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-202485"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-022-05244-8"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1177\/1759720X221124545"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.106607"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.5174"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.5377"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2008.07.010"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12267"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12128"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-017-2609-7"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu15122800"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2022.1050598"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2021.12.007"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12762"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/cei.13237"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1039\/D3SC02350H"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2007.03.028"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0066478"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/jor.24693"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2017.09.005"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox11081621"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2018.10.417"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.13191"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2148-8-19"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-1979"}],"container-title":["Journal of Pineal Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jpi.12992","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,25]],"date-time":"2024-09-25T09:16:45Z","timestamp":1727255805000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jpi.12992"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9]]},"references-count":57,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2024,9]]}},"alternative-id":["10.1111\/jpi.12992"],"URL":"https:\/\/doi.org\/10.1111\/jpi.12992","archive":["Portico"],"relation":{},"ISSN":["0742-3098","1600-079X"],"issn-type":[{"value":"0742-3098","type":"print"},{"value":"1600-079X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9]]},"assertion":[{"value":"2024-03-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e12992"}}