TRIM25 is a ubiquitin E3 ligase that functions as a central hub in innate immunity and cellular stress responses. As an ISG15 E3 ligase, it mediates Lys-63-linked polyubiquitination of pattern recognition receptors RIG-I and IFIH1, promoting interferon production during viral infection 12. TRIM25 also potentiates the antiviral protein ZAP/ZC3HAV1 through Lys-63-linked polyubiquitination required for optimal mRNA binding 34. Recent work reveals that TRIM25 functions as an RNA-binding E3 ligase that suppresses exogenous mRNAs delivered by endosomes, with activity enhanced at acidic pH, suggesting activation by endosomal rupture 5. TRIM25 accumulates in antiviral stress granules where it undergoes liquid-liquid phase separation with G3BP1, enhancing ubiquitination of antiviral substrates and RIG-I signaling 6. Beyond immunity, TRIM25 mediates estrogen action and regulates DNA replication fork restart. In cancer, TRIM25 is upregulated in glioblastoma, triple-negative breast cancer, and gastric cancer, where it promotes proliferation and chemoresistance through substrate ubiquitination—specifically targeting NONO to activate PRMT1/c-MYC signaling in glioblastoma 7 and suppressing ITPKB degradation to maintain ROS homeostasis in temozolomide-resistant glioblastoma 8. Targeting TRIM25 or its substrate interactions represents a therapeutic opportunity in these malignancies.