{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T20:32:50Z","timestamp":1778358770265,"version":"3.51.4"},"reference-count":37,"publisher":"Walter de Gruyter GmbH","issue":"1","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Intervertebral disc degeneration (IVDD) is a common cause of chronic low back pain, and ferroptosis \u2013 an iron-dependent form of cell death \u2013 has been linked to oxidative stress-induced damage in nucleus pulposus cells (NPCs). This study focuses on the role of TRIM21, an E3 ubiquitin ligase, in regulating ferroptosis during IVDD. TRIM21 expression was analyzed in clinical IVDD samples and tert-butyl hydroperoxide (TBHP)-treated NPCs. Ferroptosis was measured by assessing cell viability, Fe\n                    <jats:sup>2+<\/jats:sup>\n                    \/ROS accumulation, and lipid peroxidation. The mechanism was investigated through Co-immunoprecipitation (Co-IP), ubiquitination assays, and cycloheximide (CHX) chase experiments. Results revealed that TRIM21 was significantly upregulated in degenerated discs. Silencing TRIM21 alleviated TBHP-induced ferroptosis, reducing iron overload, ROS, and lipid peroxidation, while restoring antioxidant activity and modulating ferroptosis-related proteins. Ferrostatin-1 rescued TRIM21-overexpression-induced ferroptotic injury. Mechanistically, TRIM21 bound SLC7A11 and promoted its K48-linked ubiquitination and proteasomal degradation. SLC7A11 knockdown reversed the protective effect of TRIM21 silencing. Thus, TRIM21 exacerbates IVDD by driving ferroptosis through ubiquitin-mediated degradation of SLC7A11, highlighting its potential as a therapeutic target.\n                  <\/jats:p>","DOI":"10.1515\/biol-2025-1216","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T17:02:01Z","timestamp":1767027721000},"source":"Crossref","is-referenced-by-count":1,"title":["TRIM21 accelerates ferroptosis in intervertebral disc degeneration by promoting SLC7A11 ubiquitination and degradation"],"prefix":"10.1515","volume":"20","author":[{"given":"Wei","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Orthopedics , Jiangyin People\u2019s Hospital , Jiangyin , Jiangsu , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics , Jiangyin People\u2019s Hospital , Jiangyin , Jiangsu , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Orthopedics , Jiangyin People\u2019s Hospital , Jiangyin , Jiangsu , China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"374","published-online":{"date-parts":[[2025,12,30]]},"reference":[{"key":"2025122917015931061_j_biol-2025-1216_ref_001","doi-asserted-by":"crossref","unstructured":"Kirnaz, S, Capadona, C, Wong, T, Goldberg, JL, Medary, B, Sommer, F, et al.. Fundamentals of intervertebral disc degeneration. World Neurosurg 2022;157:264\u201373. https:\/\/doi.org\/10.1016\/j.wneu.2021.09.066.","DOI":"10.1016\/j.wneu.2021.09.066"},{"key":"2025122917015931061_j_biol-2025-1216_ref_002","doi-asserted-by":"crossref","unstructured":"Guo, W, Li, B, Zhao, J, Li, X, Wang, L. Causal associations between modifiable risk factors and intervertebral disc degeneration. Spine J 2024;24:195\u2013209. https:\/\/doi.org\/10.1016\/j.spinee.2023.10.021.","DOI":"10.1016\/j.spinee.2023.10.021"},{"key":"2025122917015931061_j_biol-2025-1216_ref_003","doi-asserted-by":"crossref","unstructured":"Silwal, P, Nguyen-Thai, AM, Mohammad, HA, Wang, Y, Robbins, PD, Lee, JY, et al.. Cellular senescence in intervertebral disc aging and degeneration: molecular mechanisms and potential therapeutic opportunities. 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Cell Biochem Biophys 2025;83:33\u201342. https:\/\/doi.org\/10.1007\/s12013-024-01468-6.","DOI":"10.1007\/s12013-024-01468-6"},{"key":"2025122917015931061_j_biol-2025-1216_ref_006","doi-asserted-by":"crossref","unstructured":"Wu, T, Teng, Y, Song, D, Yang, Y, Shen, H, Sun, X, et al.. A strategy targeting ferroptosis for mitochondrial reprogramming and intervertebral disc degeneration therapy. Theranostics 2025;15:9159\u201378. https:\/\/doi.org\/10.7150\/thno.117725.","DOI":"10.7150\/thno.117725"},{"key":"2025122917015931061_j_biol-2025-1216_ref_007","doi-asserted-by":"crossref","unstructured":"Lacoursiere, RE, Hadi, D, Shaw, GS. Acetylation, phosphorylation, ubiquitination (oh my!): following post-translational modifications on the ubiquitin road. Biomolecules 2022;12:467. https:\/\/doi.org\/10.3390\/biom12030467.","DOI":"10.3390\/biom12030467"},{"key":"2025122917015931061_j_biol-2025-1216_ref_008","doi-asserted-by":"crossref","unstructured":"Toma-Fukai, S, Shimizu, T. Structural diversity of ubiquitin E3 ligase. Molecules 2021;26:6682. https:\/\/doi.org\/10.3390\/molecules26216682.","DOI":"10.3390\/molecules26216682"},{"key":"2025122917015931061_j_biol-2025-1216_ref_009","doi-asserted-by":"crossref","unstructured":"Li, Y, Bao, L, Zheng, H, Geng, M, Chen, T, Dai, X, et al.. E3 ubiquitin ligase TRIM21 targets TIF1gamma to regulate beta-catenin signaling in glioblastoma. Theranostics 2023;13:4919\u201335. https:\/\/doi.org\/10.7150\/thno.85662.","DOI":"10.7150\/thno.85662"},{"key":"2025122917015931061_j_biol-2025-1216_ref_010","doi-asserted-by":"crossref","unstructured":"Kiss, L, James, LC. The molecular mechanisms that drive intracellular neutralization by the antibody-receptor and RING E3 ligase TRIM21. 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Oxidative stress in intervertebral disc degeneration: molecular mechanisms, pathogenesis and treatment. Cell Prolif 2023;56:e13448. https:\/\/doi.org\/10.1111\/cpr.13448.","DOI":"10.1111\/cpr.13448"},{"key":"2025122917015931061_j_biol-2025-1216_ref_019","doi-asserted-by":"crossref","unstructured":"Do, H, Baek, K. Cellular functions regulated by deubiquitinating enzymes in neurodegenerative diseases. Ageing Res Rev 2021;69:101367. https:\/\/doi.org\/10.1016\/j.arr.2021.101367.","DOI":"10.1016\/j.arr.2021.101367"},{"key":"2025122917015931061_j_biol-2025-1216_ref_020","doi-asserted-by":"crossref","unstructured":"Li, S, Jiang, W, Chen, F, Qian, J, Yang, J. The critical role of TRIM protein family in intervertebral disc degeneration: mechanistic insights and therapeutic perspectives. 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Ferrostatin-1 inhibits toll-like receptor 4\/NF-kappaB signaling to alleviate intervertebral disc degeneration in rats. Am J Pathol 2023;193:430\u201341. https:\/\/doi.org\/10.1016\/j.ajpath.2022.12.014.","DOI":"10.1016\/j.ajpath.2022.12.014"},{"key":"2025122917015931061_j_biol-2025-1216_ref_026","doi-asserted-by":"crossref","unstructured":"Zeng, F, Nijiati, S, Tang, L, Ye, J, Zhou, Z, Chen, X. Ferroptosis detection: from approaches to applications. Angew Chem Int Ed Engl 2023;62:e202300379. https:\/\/doi.org\/10.1002\/anie.202300379.","DOI":"10.1002\/anie.202300379"},{"key":"2025122917015931061_j_biol-2025-1216_ref_027","doi-asserted-by":"crossref","unstructured":"Jones, EL, Laidlaw, SM, Dustin, LB. TRIM21\/Ro52 \u2013 roles in innate immunity and autoimmune disease. 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Int Immunopharmacol 2025;160:114957. https:\/\/doi.org\/10.1016\/j.intimp.2025.114957.","DOI":"10.1016\/j.intimp.2025.114957"},{"key":"2025122917015931061_j_biol-2025-1216_ref_035","doi-asserted-by":"crossref","unstructured":"Wang, Z, Shen, N, Wang, Z, Yu, L, Yang, S, Wang, Y, et al.. TRIM3 facilitates ferroptosis in non-small cell lung cancer through promoting SLC7A11\/xCT K11-linked ubiquitination and degradation. Cell Death Differ 2024;31:53\u201364. https:\/\/doi.org\/10.1038\/s41418-023-01239-5.","DOI":"10.1038\/s41418-023-01239-5"},{"key":"2025122917015931061_j_biol-2025-1216_ref_036","doi-asserted-by":"crossref","unstructured":"Saini, KK, Chaturvedi, P, Sinha, A, Singh, MP, Khan, MA, Verma, A, et al.. Loss of PERK function promotes ferroptosis by downregulating SLC7A11 (system Xc(-)) in colorectal cancer. Redox Biol 2023;65:102833. https:\/\/doi.org\/10.1016\/j.redox.2023.102833.","DOI":"10.1016\/j.redox.2023.102833"},{"key":"2025122917015931061_j_biol-2025-1216_ref_037","doi-asserted-by":"crossref","unstructured":"Wang, Y, Feng, J, Zhao, L, Zhao, M, Wei, X, Geng, Y, et al.. Aspirin triggers ferroptosis in hepatocellular carcinoma cells through restricting NF-kappaB p65-activated SLC7A11 transcription. 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