TRIM21-Mediated Ubiquitination of FBL Suppresses PI3K/AKT Signaling and Tumor Progression in Clear Cell Renal Cell Carcinoma

Transcriptional reprogramming mediated by oncogenic C-Myc is a hallmark of clear cell renal cell carcinoma (ccRCC). By integrating single-cell RNA-seq, bulk transcriptomic, and proteomic datasets, we identified the nucleolar protein fibrillarin (FBL)—a known C-Myc target—as significantly overexpressed in ccRCC. This upregulation was associated with adverse clinical outcomes and critical for tumor cell viability. Mechanistic investigations revealed that FBL enhances ccRCC cell proliferation, motility, and tumorigenicity through activation of the PI3K/AKT signaling axis. Immunoprecipitation–mass spectrometry and molecular docking revealed tripartite motif-containing 21 (TRIM21) as a novel FBL-binding E3 ubiquitin ligase. TRIM21 catalyzed K48-linked polyubiquitination of FBL at lysine 292, accelerating its proteasomal degradation. TRIM21 overexpression reduced FBL levels, inhibited PI3K/AKT signaling, and reversed FBL-induced oncogenic phenotypes. In ccRCC tissues, TRIM21 expression was significantly downregulated and associated with unfavorable prognosis. Our findings uncover the TRIM21–FBL axis as a key regulator of ccRCC progression, providing mechanistic insight and potential therapeutic opportunities targeting ribosome biogenesis and oncogenic signaling.