TRIM21 is an E3 ubiquitin ligase that functions as a multifaceted regulator of protein homeostasis and innate immunity. Its catalytic activity depends on E2 enzymes including UBE2D1, UBE2D2, UBE2E1, and UBE2E2 1. TRIM21 mediates diverse ubiquitination events: it catalyzes K63-linked polyubiquitination of IRF3 to suppress interferon-beta production 2, monoubiquitinates IKBKB to negatively regulate NF-kappa-B signaling 3, and promotes proteasomal degradation of cell cycle inhibitor CDKN1B through SCF complex formation 4. TRIM21 also organizes autophagy machinery by serving as a platform for ULK1, BECN1, and ATG8 assembly 5, and regulates stress granule dynamics through G3BP1 ubiquitination 6. Clinically, TRIM21 exhibits contrasting roles in disease. In cancer, TRIM21 promotes PFK degradation in response to soft substrates, suppressing glycolysis in normal cells while becoming sequestered in cancer cells maintaining high metabolic rates 7. TRIM21 inhibits radiation-induced antitumor immunity by degrading VDAC2, blocking mitochondrial DNA release and cytokine responses 8. Conversely, TRIM21 depletion alleviates osteoporosis by enhancing osteoblastic differentiation through YAP1/β-catenin signaling 9. TRIM21 also demonstrates therapeutic potential as a platform for targeted protein degradation of multimeric assemblies, selectively degrading pathological tau aggregates while sparing monomers 10. Its role in sepsis involves facilitating TAB1 degradation, regulating platelet activation and microvascular thrombosis 11.