{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T20:01:59Z","timestamp":1785787319372,"version":"3.56.0"},"reference-count":35,"publisher":"National Academy of Sciences","issue":"32","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82472491"],"award-info":[{"award-number":["82472491"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["92049101"],"award-info":[{"award-number":["92049101"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the National Natural Sceince Foundation of China","award":["81972097"],"award-info":[{"award-number":["81972097"]}]},{"name":"Sichuan Science and Technology Program","award":["2025YFHZ0202"],"award-info":[{"award-number":["2025YFHZ0202"]}]},{"name":"the National Key Research and Developmental Plan","award":["2022YFC2505500"],"award-info":[{"award-number":["2022YFC2505500"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,8,11]]},"abstract":"<jats:p>Osteoarthritis (OA) lacks approved disease-modifying therapies. Here, by integrating quantitative proteomics with reanalysis of public single-cell RNA sequencing data from human articular cartilage, we identify thymidine kinase 1 (TK1) as a pathogenic regulator linking inflammatory stress to metabolic rewiring and matrix breakdown. TK1 is markedly upregulated in OA chondrocytes. Mechanistically, IL-1\u03b2 enhances S-palmitoylation of TK1 at Cys153, which promotes USP9X-dependent deubiquitination and prevents proteasomal degradation, leading to TK1 accumulation. Stabilized TK1 acts as a scaffold to potentiate JNK signaling, increase PRMT1 and PFKFB3 expression, drive excessive glycolysis, and accelerate extracellular matrix catabolism. Conversely, the depalmitoylase PPT1 destabilizes TK1 and restrains glycolytic activation. Based on this mechanism, we developed a cell-penetrating interfering peptide, Depalm-WT, which disrupts the TK1\u2013JNK interaction, promotes TK1 depalmitoylation and degradation, and suppresses downstream catabolic responses. In preclinical OA models, Depalm-WT attenuated cartilage degeneration and disease progression. These findings define a palmitoylation-stabilized TK1\u2013JNK\u2013glycolysis axis in OA and support targeted TK1 destabilization as a potential therapeutic strategy.<\/jats:p>","DOI":"10.1073\/pnas.2602136123","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T19:06:16Z","timestamp":1785783976000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Palmitoylation of TK1 exacerbates osteoarthritis by promoting JNK-mediated metabolic reprogramming"],"prefix":"10.1073","volume":"123","author":[{"given":"Zhao","family":"Zhang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/011ashp19","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Orthopaedic Surgery, Orthopaedic Research Institute, West China Hospital, West China Medical School, Sichuan University","place":["Chengdu, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoyi","family":"Zhang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/011ashp19","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Orthopaedic Surgery, Orthopaedic Research Institute, West China Hospital, West China Medical School, Sichuan University","place":["Chengdu, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yucan","family":"Ju","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/011ashp19","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Orthopaedic Surgery, Orthopaedic Research Institute, West China Hospital, West China Medical School, Sichuan University","place":["Chengdu, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaojia","family":"Zhou","sequence":"additional","affiliation":[{"name":"Animal Experimental Center of West China Hospital","place":["Chengdu, Sichuan Province, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihua","family":"Guo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00p991c53","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinwei","family":"Xie","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/011ashp19","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Orthopaedic Surgery, Orthopaedic Research Institute, West China Hospital, West China Medical School, Sichuan University","place":["Chengdu, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0456-8379","authenticated-orcid":false,"given":"Zeyu","family":"Huang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/011ashp19","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Orthopaedic Surgery, Orthopaedic Research Institute, West China Hospital, West China Medical School, Sichuan University","place":["Chengdu, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(23)00163-7"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01330-w"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)30417-9"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2025.08.004"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2023-225041"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-024-00998-z"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-01800-9"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2084"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2018.05.003"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-024-00666-x"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2017.12.002"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-025-00968-1"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-018-0124-5"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-019-0375-6"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104258"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2012.01.003"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2023-224002"},{"key":"e_1_3_4_18_2","article-title":"Detection of protein palmitoylation in cultured hippocampal neurons by immunoprecipitation and acyl-biotin exchange (ABE)","volume":"18","author":"Brigidi G. S.","year":"2013","unstructured":"G. S. Brigidi, S. X. Bamji, Detection of protein palmitoylation in cultured hippocampal neurons by immunoprecipitation and acyl-biotin exchange (ABE). J. Vis. Exp. 18, 50031 (2013).","journal-title":"J. Vis. Exp."},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1021\/cb900085z"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-024-01473-6"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.080508097"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2021-220000"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2023.03.017"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth947"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-53979-8"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01439-y"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adx6489"},{"key":"e_1_3_4_28_2","first-page":"1","article-title":"Crossing epigenetic frontiers: The intersection of novel histone modifications and diseases","volume":"9","author":"Yao W.","year":"2024","unstructured":"W. Yao, X. Hu, X. Wang, Crossing epigenetic frontiers: The intersection of novel histone modifications and diseases. Signal Transduct. Target. Ther. 9, 1\u201338 (2024).","journal-title":"Signal Transduct. Target. Ther."},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2025.102208"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-01971-5"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-57099-9"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adp7302"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2023.09.007"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44318-025-00410-7"},{"key":"e_1_3_4_35_2","unstructured":"Z. Zhang Data from \u201cCartilage from patients after knee joint arthroplasty was taken and divided into intact and damaged portions for proteomic sequencing.\u201d iProX. https:\/\/proteomecentral.proteomexchange.org\/cgi\/GetDataset?ID=PXD057507. Deposited 5 November 2024."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2602136123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T19:07:34Z","timestamp":1785784054000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2602136123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,3]]},"references-count":35,"journal-issue":{"issue":"32","published-print":{"date-parts":[[2026,8,11]]}},"alternative-id":["10.1073\/pnas.2602136123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2602136123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,3]]},"assertion":[{"value":"2026-01-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2602136123"}}