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Extracellular vesicles (EVs), though recognized as important mediators of tumor metastasis, have received limited attention into their specific functions via the mRNA profiling. Here it is reported elevated expression and selective enrichment of INAVA mRNA in both plasma\u2010 and tissue\u2010derived EVs from ovarian cancer patients, which is positively correlated with distant metastasis and poor prognosis. Functionally, INAVA mRNA, upon uptake and translation, activates normal ovarian fibroblasts (NOFs) and drives extensive peritoneum metastasis in the orthotopic xenograft mouse model. Mechanistically, INAVA competitively binds with high mobility group protein A2 (HMGA2) and consequently inhibit its interaction with vaccinia\u2010related kinase 1 (VRK1), leading to reduced HMGA2 phosphorylation on Ser105. Interestingly, this inhibitory phosphorylation stabilizes HMGA2 via blocking tripartite motif\u2010containing 21 (TRIM21) \u2010mediated K48\u2010linked ubiquitylation, and ultimately enhances the transcription of STAT3 to activate NOFs. Lastly, a cell\u2010permeable peptide that disrupts the INAVA\u2013HMGA2 interaction leads to attenuated NOF activation and provides a promising strategy for ovarian cancer therapy.<\/jats:p>","DOI":"10.1002\/advs.202500912","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T09:15:32Z","timestamp":1745399732000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The INAVA mRNA in Extracellular Vesicles Activates Normal Ovarian Fibroblasts by Phosphorylation\u2013Ubiquitylation Crosstalk of HMGA2"],"prefix":"10.1002","volume":"12","author":[{"given":"Lingkai","family":"Gu","sequence":"first","affiliation":[{"name":"Zhejiang Key Laboratory of Maternal and Infant Health Women's Hospital Zhejiang University School of Medicine  Hangzhou 310006 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