TRAF3 is a cytoplasmic E3 ubiquitin ligase that serves as a central regulator of innate immunity and inflammatory responses. As an adaptor protein, TRAF3 catalyzes Lys-63-linked polyubiquitination of substrates including ASC to activate type I interferon and inflammasome responses in toll-like receptor (TLR) and retinoic acid-inducible gene I-like receptor (RLR) signaling pathways 12. TRAF3 functions as a negative regulator of canonical NF-κB signaling downstream of TLR4, preventing excessive inflammation, while simultaneously inhibiting the alternative NF-κB pathway critical for B-cell survival and antibody isotype switching 3. Following bacterial detection, TRAF3 undergoes distinct Lys-33-linked polyubiquitination to orchestrate bacterial expulsion via exocyst complex mobilization 4. TRAF3 loss associates with dysregulated lipid metabolism and increased tumor progression in glioblastoma 5. Clinically, TRAF3 haploinsufficiency causes immunodeficiency characterized by recurrent bacterial infections, hypogammaglobulinemia, and features resembling common variable immunodeficiency 6. Additionally, TRAF3 degradation contributes to age-related bone loss through neutrophil infiltration 7, while TRAF3 suppression promotes psoriasis via enhanced IL-17A signaling 3.