TRIM3 is an E3 ubiquitin ligase that functions primarily as a tumor suppressor across multiple cancer types through diverse molecular mechanisms. The protein promotes ferroptosis in non-small cell lung cancer by facilitating K11-linked ubiquitination and proteasomal degradation of SLC7A11/xCT, leading to increased ROS and lipid peroxidation 1. TRIM3 suppresses brain tumorigenesis by attenuating Notch nuclear transport through direct binding to the Importin complex, thereby maintaining stem cell equilibrium 2. The protein also regulates autophagy as part of the CSNK2-TRIM axis, where CSNK2-mediated phosphorylation at serine 661 enables TRIM3 to inactivate the ULK1-BECN1 autophagy initiation complex 3. Paradoxically, in breast cancer, TRIM3 facilitates estrogen signaling by promoting ER alpha stability through K63-linked polyubiquitination, potentially contributing to cancer progression 4. The protein's tumor suppressor activity is further supported by its downregulation in breast cancer tissues, where reduced expression correlates with increased invasion 5. TRIM3 can form heterodimers with TRIM2, and its E3 ligase activity requires proper self-association, which is regulated by specific amino acid sequences adjacent to the RING domain 6.