Pleiotropic Roles of FBXO11 in Tumorigenesis: Implications for Targeted Therapy

F-box protein 11 (FBXO11), a critical component of the F-box protein family, serves as the substrate recognition subunit of the Skp1-Cul1-F-box (SCF) E3 ubiquitin ligase complex, orchestrates the ubiquitination and proteasomal degradation of a diverse array of substrates, thereby regulating various physiological and pathological processes. Emerging evidence reveals that FBXO11 is aberrantly expressed in multiple tumor types. Predominantly, FBXO11 functions as a potent tumor suppressor, and its downregulation is strongly correlated with tumor initiation, aggressive progression, and poor prognoses. Mechanistically, FBXO11 deficiency facilitates tumor development and metastasis by deregulating the cell cycle progression, enhancing cell migration and invasion, and driving epithelial-mesenchymal transition (EMT). However, the broad substrate spectrum of FBXO11 dictates its context-dependent roles in cancer biology, imparting significant challenges to its direct therapeutic targeting, as systemic modulation may yield unpredictable off-target or paradoxical effects. This review provides a comprehensive overview of current understanding of FBXO11 in oncology. By critically appraising its substrate diversity and functional versatility, we aim to re-evaluate the clinical translation of FBXO11, proposing that it be regarded not merely as a straightforward therapeutic target, but rather as a prognostic biomarker and a context-specific vulnerability that necessitates precision medicine strategies for effective clinical intervention.