FBXO2 (F-box protein 2) is a substrate recognition component of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex that mediates ubiquitin-dependent proteasomal degradation of target proteins 123. The protein functions by recognizing specific substrates through its F-box-associated (FBA) domain and promoting their K48- and K63-linked polyubiquitination 23. FBXO2 exhibits dual regulatory roles in disease contexts. In degenerative conditions like intervertebral disc degeneration, FBXO2 acts protectively by activating PINK1-Parkin mitophagy and promoting K27-linked ubiquitination of lipocalin-2 (LCN2) to suppress ferroptosis 4. However, in cancer, FBXO2 displays context-dependent effects: it suppresses prostate cancer by degrading oncogenic YTHDF2 1 and inhibits renal cell carcinoma through WEE1 ubiquitination 3, yet promotes hepatocellular carcinoma progression by targeting tumor suppressor USP49 for degradation and enhancing mTORC1 signaling through KPTN ubiquitination 52. FBXO2 can also be packaged into extracellular vesicles during muscle overtraining, contributing to liver fibrosis 6. These findings highlight FBXO2's complex role as both a tumor suppressor and oncogene depending on cellular context and substrate specificity.