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Bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) have emerged as key mediators in the tumor microenvironment, promoting OS progression. This study identifies a novel molecular axis centered on circRNA-0010220 within BMSC-EVs that drives OS aggressiveness. We demonstrate that BMSC-EVs are internalized by OS cells, enhancing their proliferation, migration, and invasion. High-throughput sequencing revealed circRNA-0010220 as the most significantly upregulated circRNA in EV-treated OS cells. Functional studies showed that circRNA-0010220 knockdown in BMSCs attenuated the oncogenic effects of their EVs both in vitro and in vivo. Mechanistically, circRNA-0010220 recruits the histone methyltransferase EZH2 to the CTNNBIP1 promoter, facilitating H3K27me3-mediated epigenetic silencing. The subsequent downregulation of CTNNBIP1 leads to activation of the Wnt\/\u03b2-catenin signaling pathway. This cascade was consistently observed across gain-of-function and loss-of-function experiments, and pharmacologic inhibition of \u03b2-catenin reversed the pro-tumorigenic effects. Our findings elucidate a complete signaling axis from BMSC-EVs to Wnt\/\u03b2-catenin activation via circRNA-0010220\/EZH2\/CTNNBIP1, providing new insights into the epigenetic regulation of OS progression and suggesting potential therapeutic targets.<\/jats:p>","DOI":"10.1038\/s41419-026-08655-8","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T02:36:56Z","timestamp":1774406216000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["BMSC-derived extracellular vesicles enhance osteosarcoma proliferation and metastasis via the circRNA-0010220\/\u03b2-catenin pathway"],"prefix":"10.1038","volume":"17","author":[{"given":"Runsang","family":"Pan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanyuan","family":"Ruan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangfu","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7842-0980","authenticated-orcid":false,"given":"Jianyang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3723-3188","authenticated-orcid":false,"given":"Xiaobin","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"8655_CR1","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1038\/s41572-022-00409-y","volume":"8","author":"HC Beird","year":"2022","unstructured":"Beird HC, Bielack SS, Flanagan AM, Gill J, Heymann D, Janeway KA, et al. 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This study was approved by the Human Ethics Committee of Guizhou Medical University, with the ethical approval number 202079. Ethics approval for animal work was provided by the Institutional Animal Care and Use Committee of GuiZhou Medical University, with the ethical approval number 2000631.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"376"}}