Abstract
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) frequently exhibits transcriptional reprogramming driven by oncogenic C-Myc. Fibrillarin (FBL), a nucleolar C-Myc target, is markedly upregulated in ccRCC, correlating with poor prognosis and essential for tumor cell survival. METHODS: Integrated single-cell RNA sequencing, bulk transcriptomics, and proteomics were used to identify FBL as a key target. Functional assays, immunoprecipitation-mass spectrometry, and molecular docking were performed to investigate FBL's oncogenic mechanisms and interaction with TRIM21. RESULTS: FBL promotes ccRCC cell proliferation, migration, and tumor growth via PI3K/AKT pathway activation. TRIM21 was identified as a novel FBL-binding E3 ubiquitin ligase that catalyzes K48-linked polyubiquitination of FBL at lysine 292, accelerating its proteasomal degradation. TRIM21 overexpression reduces FBL levels, inhibits PI3K/AKT signaling, and reverses FBL-induced oncogenic phenotypes. TRIM21 is downregulated in ccRCC tissues and associated with unfavorable prognosis. CONCLUSIONS: The TRIM21-FBL axis regulates ccRCC progression by modulating PI3K/AKT signaling, providing mechanistic insight and potential therapeutic targets for ribosome biogenesis and oncogenic signaling.