ITCH is an E3 ubiquitin-protein ligase that transfers ubiquitin from E2 enzymes to target substrates, catalyzing Lys-29, Lys-48, and Lys-63-linked ubiquitin conjugation 1. ITCH plays a central role in regulating inflammatory signaling by functioning as an essential component of a ubiquitin-editing complex alongside TNFAIP3, TAX1BP1, and RNF11 that controls TNF and LPS-mediated NF-κB activation through RIPK1 ubiquitination and degradation 1. Beyond inflammation, ITCH ubiquitinates diverse substrates including RIPK2 (NOD2 signaling), MAVS (antiviral responses), JUNB (Th2 cytokine production), CXCR4 (receptor trafficking), and TXNIP (apoptosis regulation), making it a critical regulator of immune responses, viral defense, and hematopoietic development 1234. ITCH also mediates influenza A virus inhibition through M1 matrix protein ubiquitination and degradation 5. Mutations in ITCH cause autoimmune disease with multisystem manifestations and facial dysmorphism, underscoring its importance in immune homeostasis. The protein's regulation of multiple signaling cascades and protein degradation pathways positions it as a central hub in inflammatory control and immune regulation.