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Isoleucyl\u2010tRNA synthetase 2 (IARS2), a member of the aminoacyl\u2010tRNA synthetase family, promotes tumorigenesis across various cancers. Herein, the effects and mechanisms of IARS2 in breast cancer were investigated. IARS2 is upregulated in breast cancer tissues compared to normal tissues, correlating with the poor prognosis of patients with breast cancer. In order to knock down and overexpress IARS2, plasmids carrying short hairpin RNA targeting IARS2 and IARS2\u2010overexpression plasmids were transfected into breast cancer cells, respectively. Our results demonstrated that silencing IARS2 repressed breast cancer cell progression. IARS2 deficiency attenuated tumor growth in MDA\u2010MB\u2010231 cell xenograft mouse models. Conversely, overexpression of IARS2 aggravated malignant cell behaviors in vitro and accelerated tumor growth in vivo. Mechanistically, IARS2 depletion stimulated ubiquitination\u2010mediated degradation of \u03b2\u2010catenin in breast cancer cells. Notably, the \u03b2\u2010catenin inhibitor XAV\u2010939 reversed IARS2\u2010driven breast cancer malignant progression. Furthermore, differentially expressed genes were identified in IARS2\u2010overexpressed breast cancer cells with or without XAV\u2010939 in the light of mRNA\u2010seq results. Overall, our findings uncovered that silencing IARS2 blocked the \u03b2\u2010catenin signaling axis, thereby impeding breast cancer progression. IARS2 might become a promising novel therapeutic target for breast cancer intervention.<\/jats:p>","DOI":"10.1002\/ccs3.70094","type":"journal-article","created":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T13:40:42Z","timestamp":1783863642000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unveiling isoleucyl\u2010tRNA synthetase 2 as a novel driver of breast cancer via \u03b2\u2010catenin pathway activation"],"prefix":"10.1002","volume":"20","author":[{"given":"Xi","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Breast Surgery The First Affiliated Hospital of Dalian Medical University  Dalian China"},{"name":"Department of Plastic Surgery The First Affiliated Hospital of Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery The First 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