biostudies-literatureFu LShenzhen Medical Research FundNational Science Fund for Distinguished Young ScholarsGuangdong Basic and Applied Basic Research FoundationLeading Innovative Talents in ChangzhouBasic and Applied Basic Research Foundation of Guangdong ProvinceGuangzhou Youth Medical Innovation Practice Research ProgramNational Natural Science Foundation of ChinaChina Postdoctoral Science FoundationNatural Science Research of Jiangsu Higher Education Institutions of ChinaMedical Scientific Research Foundation of Guangdong Province of ChinaResearch Foundation of Guangzhou Women and Children's Medical Center for Clinical DoctorsNatural Science Foundation of Jiangsu Provincee06367https://www.ebi.ac.uk/biostudies/studies/S-EPMC12667553biostudies-literatureUnknown12(44)Renal cell carcinoma (RCC) remains a formidable clinical challenge, characterized by a high propensity for metastasis and the frequent emergence of intrinsic or acquired resistance to targeted therapies. However, the molecular mechanisms underlying sunitinib resistance and tumor progression in RCC are not fully understood. This study aims to identify Twinfilin actin-binding protein (TWF2) as a key mediator of tumor aggressiveness and therapeutic resistance. TWF2 expression is markedly upregulated in RCC cells, particularly in sunitinib-resistant subtypes, and significantly associated with poor prognosis and therapeutic nonresponsiveness. Functional analyses demonstrate that TWF2 promotes RCC cell invasion, migration, metastasis, and sunitinib resistance by inhibiting the Hippo signaling. Mechanistically, TWF2 interacts with Yes-associated protein (YAP) via the binding residues: TWF2 M99 and YAP M225. By competitively displacing large tumor suppressor kinase 1, TWF2 prevents YAP ubiquitination and degradation, leading to its stabilization and subsequent nuclear translocation. Mutation of the M99 residue abolishes the tumor-promoting activity of TWF2. Furthermore, salvianolic acid E is identified as a small-molecule inhibitor of the TWF2-YAP interaction, and synergistically enhances sunitinib efficacy in RCC cell lines and patient-derived xenograft models. These findings highlight TWF2 as a promising therapeutic target for overcoming drug resistance in RCC.Advanced science (Weinheim, Baden-Wurttemberg, Germany)TWF2 Drives Tumor Progression and Sunitinib Resistance in Renal Cell Carcinoma through Hippo Signaling Suppression.PMC126675532023A15152200938237343323KJB3200182023M73037482272862BK20240342824036062023QNYXZD005823031638240396882473417A202520682472957817250162023M744047A24030052025A15150126632023BS017CQ202201292024M76379382403280Shu GHuang KZhang LChen WChen YGuan BWei JYang JPan YFeng ZChen JChen MLiao WZhou XLi SZhang ZLuo JFeng HTan YYu ALu JLuo LLin HFu LYe KLin MfalseTWF2 Drives Tumor Progression and Sunitinib Resistance in Renal Cell Carcinoma through Hippo Signaling Suppression.Renal cell carcinoma (RCC) remains a formidable clinical challenge, characterized by a high propensity for metastasis and the frequent emergence of intrinsic or acquired resistance to targeted therapies. However, the molecular mechanisms underlying sunitinib resistance and tumor progression in RCC are not fully understood. This study aims to identify Twinfilin actin-binding protein (TWF2) as a key mediator of tumor aggressiveness and therapeutic resistance. TWF2 expression is markedly upregulated in RCC cells, particularly in sunitinib-resistant subtypes, and significantly associated with poor prognosis and therapeutic nonresponsiveness. Functional analyses demonstrate that TWF2 promotes RCC cell invasion, migration, metastasis, and sunitinib resistance by inhibiting the Hippo signaling. Mechanistically, TWF2 interacts with Yes-associated protein (YAP) via the binding residues: TWF2 M99 and YAP M225. By competitively displacing large tumor suppressor kinase 1, TWF2 prevents YAP ubiquitination and degradation, leading to its stabilization and subsequent nuclear translocation. Mutation of the M99 residue abolishes the tumor-promoting activity of TWF2. Furthermore, salvianolic acid E is identified as a small-molecule inhibitor of the TWF2-YAP interaction, and synergistically enhances sunitinib efficacy in RCC cell lines and patient-derived xenograft models. These findings highlight TWF2 as a promising therapeutic target for overcoming drug resistance in RCC.2025-01-01T00:00:00Z2025 Nov2026-06-30T03:36:39.392Z2026-06-30T03:34:31.2ZS-EPMC126675534094808510.1002/advs.202506367