HERC6 is an E3 ubiquitin-protein ligase that functions as a critical regulator of innate antiviral immunity through ISGylation-mediated post-translational modification 1. As an interferon-stimulated gene (ISG) product, HERC6 catalyzes the covalent attachment of ISG15 to multiple pattern recognition receptors and signaling proteins, stabilizing them against proteasomal degradation 1234. Specifically, HERC6 mediates ISGylation of STING at K150, preventing K48-linked ubiquitination and promoting type I interferon responses to viral pathogens like herpes simplex virus 1 1. Additionally, HERC6 enhances NLRP3 inflammasome activation through ISGylation, controlling inflammatory responses during infection 2. HERC6 also facilitates cGAS and MDA5 activation, amplifying antiviral signaling cascades 34. Evolutionary analysis reveals HERC6 has undergone strong adaptive evolution in mammals, suggesting historical pathogen-driven selection 5. Disease relevance includes lupus nephritis, where HERC6 emerges as a hub gene linked to immune activation and inflammation 6. HERC6 deficiency impairs antiviral defenses and increases susceptibility to viral infection, highlighting its clinical significance in host-pathogen interactions 13.