TRIM25 is a dual-function E3 ligase that catalyzes both ubiquitination and ISGylation, playing crucial roles in antiviral immunity and cellular stress responses 1 2. As a key component of innate immunity, TRIM25 mediates K63-linked polyubiquitination of RIG-I and other pattern recognition receptors, activating interferon signaling pathways essential for antiviral defense 2 3. The protein exhibits pH-dependent RNA binding activity, with increased affinity at acidic conditions, enabling surveillance of exogenous mRNAs delivered via endosomes 1. TRIM25 undergoes liquid-liquid phase separation and associates with antiviral stress granules, where its co-condensation with G3BP1 enhances ubiquitination activity toward multiple antiviral proteins 2. Beyond immunity, TRIM25 regulates diverse cellular processes including autophagy through TFEB ubiquitination 4, oxidative stress response via Keap1 degradation and Nrf2 activation 5, and lipid metabolism through INSIG1 targeting 6. Clinically, TRIM25 expression correlates with chemotherapy resistance in multiple cancers and poor patient outcomes, making it a potential therapeutic target 4 5 6. The protein's neddylation at K117 modulates its E3 ligase activity by reducing steric hindrance in the RING domain 4.