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However, the molecular mechanisms underlying sunitinib resistance and tumor progression in RCC are not fully understood. This study aims to identify Twinfilin actin\u2010binding protein (\n                    <jats:italic>TWF2<\/jats:italic>\n                    ) as a key mediator of tumor aggressiveness and therapeutic resistance.\n                    <jats:italic>TWF2<\/jats:italic>\n                    expression is markedly upregulated in RCC cells, particularly in sunitinib\u2010resistant subtypes, and significantly associated with poor prognosis and therapeutic nonresponsiveness. Functional analyses demonstrate that\n                    <jats:italic>TWF2<\/jats:italic>\n                    promotes RCC cell invasion, migration, metastasis, and sunitinib resistance by inhibiting the Hippo signaling. Mechanistically,\n                    <jats:italic>TWF2<\/jats:italic>\n                    interacts with Yes\u2010associated protein (YAP) via the binding residues:\n                    <jats:italic>TWF2<\/jats:italic>\n                    M99 and YAP M225. By competitively displacing large tumor suppressor kinase 1,\n                    <jats:italic>TWF2<\/jats:italic>\n                    prevents YAP ubiquitination and degradation, leading to its stabilization and subsequent nuclear translocation. Mutation of the M99 residue abolishes the tumor\u2010promoting activity of\n                    <jats:italic>TWF2<\/jats:italic>\n                    . Furthermore, salvianolic acid E is identified as a small\u2010molecule inhibitor of the\n                    <jats:italic>TWF2<\/jats:italic>\n                    \u2013YAP interaction, and synergistically enhances sunitinib efficacy in RCC cell lines and patient\u2010derived xenograft models. These findings highlight\n                    <jats:italic>TWF2<\/jats:italic>\n                    as a promising therapeutic target for overcoming drug resistance in RCC.\n                  <\/jats:p>","DOI":"10.1002\/advs.202506367","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T08:21:50Z","timestamp":1757924510000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<i>TWF2<\/i>\n                    Drives Tumor Progression and Sunitinib Resistance in Renal Cell Carcinoma through Hippo Signaling Suppression"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8038-4742","authenticated-orcid":false,"given":"Liangmin","family":"Fu","sequence":"first","affiliation":[{"name":"Department of Urology The First Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou Guangdong 518880 China"},{"name":"Digestive Diseases Center Guangdong Provincial 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