TNFAIP3 (A20) is a ubiquitin-editing enzyme with dual deubiquitinase and ubiquitin ligase activities that functions as a critical negative regulator of immune activation 1. The protein terminates inflammatory signaling by deubiquitinating key substrates including RIPK1, TRAF6, and MALT1, thereby preventing sustained NF-κB pathway activation downstream of TNF, IL-1β, and Toll-like receptor signaling 1. TNFAIP3 operates within a protein complex with RNF11, ITCH, and TAX1BP1 to ensure transient inflammatory responses and prevent excessive immune activation. Disease relevance is substantial: TNFAIP3 germline variants associate with systemic lupus erythematosus across multiple ethnic populations 23, while somatic mutations promote B-cell lymphoma development 1. A20 haploinsufficiency (HA20), caused by heterozygous TNFAIP3 loss, represents an autoinflammatory disorder with diverse clinical manifestations including recurrent fever, mucosal ulcers, and gastrointestinal symptoms in 177 documented cases 4. HA20 also skews immune repertoires toward self-reactive lymphocytes through a TNF/A20/NF-κB feedback loop, with potential progression to lymphoma 5. Clinically, HA20 responds to TNF inhibitors and anti-inflammatory agents 46. Additionally, TNFAIP3 inactivation in cancer cells enhances anti-tumor immunity by promoting T-cell recruitment and activation 7, suggesting therapeutic potential in immuno-oncology.