TRIM21-Mediated ubiquitination of FBL suppresses PI3K/AKT signaling and tumor progression in clear cell renal cell carcinoma

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. 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. 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. 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.