TRIM50 is an E3 ubiquitin ligase that functions as a multifaceted tumor suppressor regulating cellular homeostasis through ubiquitin-dependent and independent mechanisms. Structurally, TRIM50 contains a RING domain essential for E3 ligase activity and a B-box domain that mediates protein interactions 1. Primary Function: TRIM50 catalyzes K63-linked polyubiquitination of Beclin-1, enhancing its interaction with ULK1 to promote starvation-induced autophagy initiation 2. It also ubiquitinates p62/SQSTM1, facilitating aggresome-associated protein clearance through HDAC6 interaction 3. Additionally, TRIM50 mediates K48-linked ubiquitination of Src, targeting it for proteasomal degradation 1. Disease Relevance: TRIM50 is consistently downregulated across multiple malignancies including gastric cancer, triple-negative breast cancer, and hepatocellular carcinoma 456. In gastric cancer, TRIM50 ubiquitinates PGK1 to suppress glycolysis and inhibit tumor-associated macrophage M2 polarization, impairing invasion 4. TRIM50 ubiquitinates JUP, preventing its nuclear translocation and MYC pathway activation 7. In ovarian cancer, TRIM50 suppresses Src-dependent progression 1. Clinical Significance: TRIM50 expression inversely correlates with cancer stage, grade, and metastatic status 1. The MAZ/METTL3 axis represses TRIM50 through m6A-dependent mechanisms in hepatocellular carcinoma 68, suggesting TRIM50 restoration as a therapeutic strategy. TRIM50 correlates with immune infiltration and patient prognosis in HCC 8.