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CircRNAs regulate gene expression via RNA\u2010binding proteins (RBPs) and also exert biological effects through peptide encoding. CircPVT1 has been previously identified as an oncogenic circRNA. This study identified that circPVT1 encodes a 104\u2010amino acid peptide, termed cP104aa. Functional assays showed that circPVT1 and the cP104aa peptide enhance RCC cell proliferation, invasion, migration, and lung metastasis both in vitro and in vivo. Mechanistically, the cP104aa peptide interacts with HNRNPK, leading to reduced c\u2010MYC ubiquitination and increased c\u2010MYC expression. Additionally, circPVT1 directly associates with EIF4A3, facilitating the expression of the target gene c\u2010MYC. Furthermore, axitinib is shown to target the degradation of the cP104aa peptide. These findings reveal a novel mechanism by which circPVT1 contributes to RCC, highlighting the potential of the cP104aa peptide as a therapeutic target. Axitinib may serve as an effective therapeutic agent for patients with advanced RCC exhibiting high cP104aa expression.<\/jats:p>","DOI":"10.1002\/advs.202501211","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T18:11:27Z","timestamp":1758219087000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["CircPVT1 Promotes Lung Metastasis and Tumor Progression in Renal Cell Carcinoma by Encoding the cP104aa Peptide and Targeting EIF4A3"],"prefix":"10.1002","volume":"12","author":[{"given":"Houliang","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Urology Affiliated Zhongda Hospital of Southeast University  Nanjing 210009 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Urology The First Affiliated Hospital of USTC Division of Life Sciences and Medicine 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