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In this study, we report that circFUNDC1, a nuclear circular RNA, is markedly downregulated in nucleus pulposus cells (NPCs) from patients with end-stage IVDD. CircFUNDC1 is derived from the gene encoding the FUN14 domain-containing 1 (FUNDC1) protein, which is essential for mitophagy and cell survival. Functional analyses reveal that circFUNDC1 plays a crucial role in maintaining extracellular matrix homeostasis by enhancing the expression of anabolic factors in NPCs. Additionally, we identified the transcriptional regulator cyclin-dependent kinase 9 (CDK9) as a novel binding partner for circFUNDC1. Binding with circFUNDC1 recruits CDK9 via complementary nucleotides to the FUNDC1 promoter to stimulate the production of full-length FUNDC1 mRNAs and proteins, forming a positive feedback loop. Overexpression of circFUNDC1 protects NPCs from oxidative stress by promoting mitophagy, reducing reactive oxygen species levels, and inhibiting cellular senescence. Moreover, circFUNDC1 overexpression delays the onset of IVDD in an ex-vivo culture model. This study is the first to demonstrate that circFUNDC1 is vital for protecting NPCs from oxidative stress, suggesting circFUNDC1 as a potential therapeutic target for IVDD.<\/jats:p>","DOI":"10.1038\/s41419-025-07425-2","type":"journal-article","created":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T08:36:26Z","timestamp":1739435786000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["CircFUNDC1 interacts with CDK9 to promote mitophagy in nucleus pulposus cells under oxidative stress and ameliorates intervertebral disc degeneration"],"prefix":"10.1038","volume":"16","author":[{"given":"Tianyuan","family":"Gu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoming","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasper H. 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Bioact Mater. 2023;23:247\u201360.","journal-title":"Bioact Mater"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07425-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07425-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07425-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T08:41:44Z","timestamp":1739436104000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07425-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,13]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["7425"],"URL":"https:\/\/doi.org\/10.1038\/s41419-025-07425-2","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,13]]},"assertion":[{"value":"6 August 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 January 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 February 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 February 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study was conducted in compliance with the principles of the Declaration of Helsinki. All methods were performed in accordance with the relevant guidelines and regulations. Informed consent was obtained from all participants. All animal protocols were performed in accordance with standard ethical guidelines as approved by the Ethics Committee of Institutional Animal Care and Use Committee (IACUC, ZJCLA-20010647). Ethics approval for human subjects numbered 20220103-51 was provided from Ethics Committee of Sir Run Run Shaw Hospital, affiliated with Zhejiang University School of Medicine Ethics. Written informed consent from human research participants for the publication of the images has been obtained.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"94"}}