{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T14:45:47Z","timestamp":1792334747025,"version":"4.4.0"},"reference-count":69,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T00:00:00Z","timestamp":1792281600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T00:00:00Z","timestamp":1792281600000},"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":["82470748"],"award-info":[{"award-number":["82470748"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82070752"],"award-info":[{"award-number":["82070752"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82170939"],"award-info":[{"award-number":["82170939"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007162","name":"Guangdong Provincial Department of Science and Technology","doi-asserted-by":"publisher","award":["202201020273"],"award-info":[{"award-number":["202201020273"]}],"id":[{"id":"10.13039\/501100007162","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Osteoporosis is a prevalent age\u2010 and disease\u2010associated skeletal disorder characterized by bone loss, remodeling imbalance, and vascular niche deterioration, yet how endothelial redox dysfunction drives this process remains unclear. Here, we identify mitochondrial thioredoxin\u20102 (TRX2) as an endothelial safeguard against osteoporotic bone loss. TRX2 was markedly reduced in aging bone vascular endothelial cells, and endothelial Trx2 deficiency accelerated skeletal degeneration by suppressing osteogenic activity and enhancing osteoclastogenesis. Mechanistically, TRX2 directly bound FOXO3a through a redox\u2010sensitive Cys90\u2013Cys31 disulfide interaction, retaining FOXO3a at the mitochondrial outer membrane and limiting its nuclear translocation. TRX2 loss or oxidative stress disrupted this complex, enabling FOXO3a\u2010dependent transcriptional activation of tumor necrosis factor\u2013related apoptosis\u2010inducing ligand (TRAIL) and generating a pro\u2010osteoclastogenic vascular niche. TRAIL neutralization or endothelial TRX2 restoration attenuated ovariectomy\u2010induced osteoporosis by preserving angiogenic\u2013osteogenic coupling. These findings establish the endothelial TRX2\u2013FOXO3a\u2013TRAIL axis as a vascular redox checkpoint and potential therapeutic target for osteoporosis.<\/jats:p>","DOI":"10.1002\/advs.78304","type":"journal-article","created":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T14:27:28Z","timestamp":1792333648000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Thioredoxin\u20102 Alleviates Osteoporosis by Restraining FOXO3a Nuclear Translocation"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-7353-9669","authenticated-orcid":false,"given":"Chi","family":"Zhan","sequence":"first","affiliation":[{"name":"School of Medicine Guangzhou First People's Hospital The Second Affiliated Hospital South China University of Technology  Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Stomatology Hospital of Stomatology Guanghua School of Stomatology Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaocai","family":"Zhou","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Stomatology Hospital of Stomatology Guanghua School of Stomatology Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5767-4714","authenticated-orcid":false,"given":"Yue","family":"Ding","sequence":"additional","affiliation":[{"name":"School of Medicine Guangzhou First People's Hospital The Second Affiliated Hospital South China University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0780-0604","authenticated-orcid":false,"given":"Rong","family":"Lian","sequence":"additional","affiliation":[{"name":"School of Medicine Guangzhou First People's Hospital The Second Affiliated Hospital South China University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Li","sequence":"additional","affiliation":[{"name":"School of Medicine Guangzhou First People's Hospital The Second Affiliated Hospital South China University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3085-6719","authenticated-orcid":false,"given":"Xintong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Stomatology Hospital of Stomatology Guanghua School of Stomatology Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0401-590X","authenticated-orcid":false,"given":"Jie","family":"Cao","sequence":"additional","affiliation":[{"name":"School of Medicine Guangzhou First People's Hospital The Second Affiliated Hospital South China University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhonghui","family":"Tang","sequence":"additional","affiliation":[{"name":"Zhongshan School of Medicine Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1586-3741","authenticated-orcid":false,"given":"Zhengmei","family":"Lin","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Stomatology Hospital of Stomatology Guanghua School of Stomatology Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Song","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Stomatology Hospital of Stomatology Guanghua School of Stomatology Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3207-1295","authenticated-orcid":false,"given":"Feng","family":"He","sequence":"additional","affiliation":[{"name":"School of Medicine Guangzhou First People's Hospital The Second Affiliated Hospital South China University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,18]]},"reference":[{"key":"e_1_2_9_2_1","first-page":"89","article-title":"Osteoporosis A Review","volume":"334","author":"Morin S. N.","year":"2025","journal-title":"JAMA"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010med\u2010050124\u2010040555"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2023.102130"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc19\u20100925"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2024.11.013"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584\u2010022\u201000793\u20105"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.46.suppl_1.i1"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213\u20108587(21)00347\u20108"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010023\u201001467\u20108"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.02.002"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584\u2010021\u201000682\u20103"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201034425\u2010z"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556\u2010023\u201001240\u20107"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis\u20102020\u2010218089"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.34126"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574\u2010024\u201001039\u2010y"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41413\u2010024\u201000346\u20104"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.146728"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.114834"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.11.001"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010022\u201001923\u2010y"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2024.102505"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(21)02646\u20105"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213\u20108587(22)00012\u20102"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010024\u201002095\u20106"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2024.103032"},{"key":"e_1_2_9_28_1","doi-asserted-by":"crossref","DOI":"10.1084\/jem.20201416","article-title":"Mitophagy\u2010Mediated Adipose Inflammation Contributes to type 2 Diabetes with Hepatic Insulin Resistance","volume":"218","author":"He F.","year":"2021","journal-title":"Journal of Experimental Medicine"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2007.060960"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.108.180349"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201035262\u2010w"},{"key":"e_1_2_9_32_1","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1038\/s41556-024-01545-1","article-title":"Specialized Post\u2010Arterial Capillaries Facilitate Adult Bone Remodelling","volume":"26","author":"Mohanakrishnan V.","year":"2024","journal-title":"Nature Cell Biology"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13145"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.07.007"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfj175"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2418023122"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2018.04.008"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.08.039"},{"key":"e_1_2_9_39_1","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1016\/j.molimm.2007.12.003","article-title":"TNF\u2010Related Apoptosis\u2010Inducing Ligand (TRAIL) Induces Osteoclast Differentiation from Monocyte\/Macrophage Lineage Precursor Cells","volume":"45","author":"Yen M. L.","year":"2008","journal-title":"Molecular Immunology"},{"key":"e_1_2_9_40_1","doi-asserted-by":"crossref","first-page":"521","DOI":"10.3390\/cells13060521","article-title":"TNF\u2010Related Apoptosis\u2010Inducing Ligand: Non\u2010Apoptotic Signalling","volume":"13","author":"Guerrache A.","year":"2024","journal-title":"Cells"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13146"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.14139"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13601"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4773"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1089\/scd.2024.0055"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000130525.37646.a7"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2015.06.019"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2014.6056"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3507"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2010.01.001"},{"key":"e_1_2_9_51_1","doi-asserted-by":"crossref","DOI":"10.1111\/acel.13367","article-title":"TRIM33 Protects Osteoblasts from Oxidative Stress\u2010Induced Apoptosis in Osteoporosis by Inhibiting FOXO3a Ubiquitylation and Degradation","volume":"20","author":"Zou D. B.","year":"2021","journal-title":"Aging Cell"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI68049"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010019\u20101353\u20103"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0809493"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213\u20108587(17)30138\u20109"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010023\u201001943\u20107"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059\u2010017\u20101382\u20100"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010021\u201001206\u2010w"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2020.05.010"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010019\u201041695\u2010z"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010018\u20100414\u20106"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010020\u20100591\u20103"},{"key":"e_1_2_9_63_1","doi-asserted-by":"crossref","DOI":"10.1093\/bioadv\/vbac016","article-title":"decoupleR: Ensemble of Computational Methods to Infer Biological Activities from Omics Data","volume":"2","author":"Badia I. M. P.","year":"2022","journal-title":"Bioinformatics Advances"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010021\u201001274\u20105"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059\u2010020\u20101949\u2010z"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkag470"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000033829"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad965"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010024\u201007487\u2010w"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201028865\u2010w"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.78304","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.78304","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.78304","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T14:27:31Z","timestamp":1792333651000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.78304"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,18]]},"references-count":69,"alternative-id":["10.1002\/advs.78304"],"URL":"https:\/\/doi.org\/10.1002\/advs.78304","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,18]]},"assertion":[{"value":"2026-06-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e78304"}}