DTX4 (deltex E3 ubiquitin ligase 4) is an E3 ubiquitin ligase that functions as a negative regulator of innate immune responses and plays contextual roles in viral persistence and cancer progression. Structurally, DTX4 contains a RING domain characteristic of the DELTEX family and a C-terminal domain that may recognize modified substrates 1. Mechanistically, DTX4 mediates K48-linked polyubiquitination of multiple targets. In antiviral immunity, DTX4 promotes proteasomal degradation of TBK1/IKKε in an NLRP4-dependent manner, thereby suppressing type I interferon production 2. In HBV infection, p-STAT3-elevated DTX4 facilitates ubiquitination and degradation of APOBEC3B, promoting HBV cccDNA stability and viral replication 3. DTX4 also regulates Notch signaling by mediating ubiquitylation of ligand-activated Notch1, facilitating bilateral endocytosis and intracellular ADAM10 processing 4. Disease relevance spans multiple conditions. DTX4 expression correlates with thyroid cancer progression through the DTX4/SCD1 axis, promoting cell proliferation and migration 5. DTX4 dysregulation has been implicated in ureteropelvic junction obstruction-associated renal fibrosis 6. DTX4 is part of the broader DELTEX family involved in oncogenic processes beyond Notch signaling 7. Clinically, DTX4 and downstream effectors represent potential therapeutic targets for HBV treatment, thyroid cancer, and conditions involving excessive innate immune activation.