{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T06:30:27Z","timestamp":1792045827465,"version":"4.4.0"},"reference-count":69,"publisher":"Wiley","issue":"36","license":[{"start":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T00:00:00Z","timestamp":1754956800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T00:00:00Z","timestamp":1754956800000},"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":["82302725"],"award-info":[{"award-number":["82302725"]}],"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":["82272537"],"award-info":[{"award-number":["82272537"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Intervertebral disc degeneration (IVDD), a leading cause of chronic low back pain, arises from nucleus pulposus (NP) cell dysfunction due to oxidative stress\u2010induced mitophagy impairment and ferroptosis, though regulatory mechanisms remain unclear. F\u2010box only protein 2 (FBXO2), a Kruppel\u2010like factor 10 (KLF10)\u2010regulated F\u2010box protein, is downregulated in degenerated human NP tissues and correlates with disease severity. Overexpression of FBXO2 restores extracellular matrix (ECM) homeostasis by promoting matrix component synthesis and inhibiting catabolic enzymes, while its knockdown exacerbates ECM degradation. Under oxidative stress, FBXO2 activates PTEN\u2010induced putative kinase 1 (PINK1)\/Parkin\u2010dependent mitophagy, restoring mitochondrial membrane potential and reducing reactive oxygen species (ROS) accumulation. Proteomics reveals that FBXO2 suppresses ferroptosis by attenuating lipid peroxidation, glutathione depletion, and iron overload. Mechanistically, FBXO2 binds lipocalin\u20102 (LCN2) via its FBA domain, promoting K27\u2010linked polyubiquitination to drive proteasomal degradation of this ferroptosis inducer. FBXO2 co\u2010expression reverses LCN2\u2010induced mitochondrial dysfunction and ferroptosis markers. In vivo, adeno\u2010associated virus 9 (AAV9)\u2010mediated overexpression of FBXO2 ameliorates IVDD in rats, whereas FBXO2 knockout (KO) mice exhibit exacerbated IVDD. LCN2 silencing in FBXO2\u2010deficient mice partially restores disc integrity and matrix component expression. These findings identify FBXO2 as a dual regulator coordinating mitophagy activation and ferroptosis suppression, offering therapeutic potential for IVDD progression.<\/jats:p>","DOI":"10.1002\/advs.202506150","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T08:50:15Z","timestamp":1754988615000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["FBXO2 Alleviates Intervertebral Disc Degeneration via Dual Mechanisms: Activating PINK1\u2010Parkin Mitophagy and Ubiquitinating LCN2 to Suppress Ferroptosis"],"prefix":"10.1002","volume":"12","author":[{"given":"Tongde","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Spine Surgery Shanghai East Hospital School of Medicine Tongji University  Shanghai 200092 China"},{"name":"Department of Clinic of Spine Center Xinhua Hospital School of Medicine Shanghai Jiao Tong University  1665 Kongjiang Road Shanghai 200092 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nephrology Shanghai East Hospital School of Medicine Tongji University  Shanghai 200092 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beiduo","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Spine Surgery Shanghai East Hospital School of Medicine Tongji University  Shanghai 200092 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Spine Surgery Shanghai East Hospital School of Medicine Tongji University  Shanghai 200092 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqi","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Spine Surgery Shanghai East Hospital School of Medicine Tongji University  Shanghai 200092 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongzhou","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology West China Second University Hospital Sichuan University  Chengdu Sichuan 610041 China"},{"name":"Department of Pediatric Cardiology Xinhua Hospital School of Medicine Shanghai Jiao Tong University  1665 Kongjiang Road Shanghai 200092 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Spine Surgery Shanghai East Hospital School of Medicine Tongji University  Shanghai 200092 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7100-8806","authenticated-orcid":false,"given":"Desheng","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Spine Surgery Shanghai East Hospital School of Medicine Tongji University  Shanghai 200092 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,12]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00733-9"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12891-016-1071-2"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.spinee.2024.05.018"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30925-9"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/BRS.0b013e3181cd588c"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jot.2022.10.009"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jsp2.1076"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.brs.0000231761.73859.2c"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-022-00732-0"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.30039"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2020.1822097"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202401103"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.06.006"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2022.102304"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-021-03774-1"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2022.2139080"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2021.01.002"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/BRS.0000000000003942"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.042"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01606-1"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2022.08.018"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41413-024-00317-9"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jot.2024.08.016"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2024.113895"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax3769"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-021-00448-5"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-090120-013613"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2000-1-5-reviews3002"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03197-9"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.embor.7400351"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3582"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jot.2021.04.003"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2013.10.001"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2013.160"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2024.102323"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202207216"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2020.1797280"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102707"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature00890"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-nutr-071816-064559"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-023-01429-1"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2022.2062887"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1136\/bjsports-2021-104749"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcp2032396"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41413-023-00280-x"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/jsp2.1231"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41413-020-00125-x"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2020.04.016"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510300620"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13418"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11636-5"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2022111372"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0199-y"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202404275"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2019.01.009"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.06.003"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2020.08.029"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2021.06.010"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexmp.2020.104570"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03104"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27452-9"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-57873-9"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2015.12.010"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-022-00907-9"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1097\/00007632-200109010-00011"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.68"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1002\/jor.23637"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.3171\/2009.2.SPINE08925"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2018.10.011"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202506150","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.202506150","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202506150","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T19:12:22Z","timestamp":1785438742000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202506150"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,12]]},"references-count":69,"journal-issue":{"issue":"36","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["10.1002\/advs.202506150"],"URL":"https:\/\/doi.org\/10.1002\/advs.202506150","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,12]]},"assertion":[{"value":"2025-04-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e06150"}}