Background <p>Renal cell carcinoma (RCC) is a common lethal malignancy of the urinary system with a complex pathogenesis. Among its subtypes, clear cell renal cell carcinoma (ccRCC) represents the predominant pathological type. Circular RNAs (circRNAs), a class of covalently closed RNA molecules, play critical roles in various cancers. CircCCDC66 has been reported to exhibit aberrant expression and participate in tumor progression in multiple malignancies; however, its functional role and underlying mechanisms in clear cell renal cell carcinoma (ccRCC) remain unclear. This study aimed to investigate the role of circCCDC66 in ccRCC and its underlying regulatory mechanism.</p> Methods <p>CircCCDC66, miR-1278, and HOXA13 expression levels in ccRCC tissues and cell lines were measured using quantitative real-time PCR (qPCR). Cell proliferation, migration, and invasion were assessed through colony formation, CCK-8, Transwell, and wound healing assays. Western blotting was conducted to evaluate the expression of epithelial-mesenchymal transition (EMT)-related markers, including E-cadherin, N-cadherin, Vimentin, and HOXA13. Bioinformatics tools, such as StarBase and CircInteractome, were utilized to predict the binding sites between circCCDC66 and miR-1278, as well as between miR-1278 and HOXA13; these predictions were further validated using dual-luciferase reporter assays. Additionally, a ccRCC xenograft tumor model was established to investigate the in vivo regulatory effect of circCCDC66 on tumor growth.</p> Results <p>CircCCDC66 and HOXA13 were significantly upregulated in ccRCC tissues and cell lines, whereas miR-1278 expression was markedly downregulated. Knockdown of circCCDC66 significantly inhibited ccRCC cell proliferation, migration, invasion, and EMT progression. In vivo, experiments further confirmed that circCCDC66 overexpression promoted tumor growth. Mechanistically, dual-luciferase reporter and RNA immunoprecipitation assays demonstrated that circCCDC66 directly binds to miR-1278, and inhibition of miR-1278 rescued the circCCDC66 knockdown-induced suppression of proliferation and metastasis. Furthermore, dual-luciferase reporter assays confirmed the binding between miR-1278 and HOXA13. Rescue experiments revealed that circCCDC66 functions as a competing endogenous RNA (ceRNA) by sponging miR-1278, thereby upregulating HOXA13 expression and facilitating ccRCC progression.</p> Conclusion <p>CircCCDC66 is upregulated in ccRCC and promotes tumorigenesis and progression by acting as a miR-1278 sponge to derepress HOXA13 expression.</p>