PELI1 (Pellino E3 ubiquitin protein ligase 1) is a highly conserved E3 ubiquitin ligase that plays crucial roles in immune signaling and inflammation regulation. The protein catalyzes both K48-linked and K63-linked polyubiquitination of diverse target proteins to modulate cellular responses 1. PELI1 functions as a key regulator in innate immune pathways, particularly TLR and IL-1 signaling cascades 1. The enzyme mediates K63-linked ubiquitination of IRAK2, leading to its degradation and suppression of MAPK/NF-κB signaling in airway inflammation 2. Additionally, PELI1 targets STAT3 for K63-linked ubiquitination, resulting in pathogenic STAT3 activation in macrophages during colitis and colitis-associated cancer development 3. In pulmonary hypertension, PELI1 facilitates K48-linked ubiquitination and proteasomal degradation of FOXP1, thereby relieving transcriptional suppression of IL-6 and promoting macrophage activation 4. The protein also regulates skin-resident IL-17A-producing T cells in psoriasis through NF-κB pathway activation 5. PELI1 demonstrates context-dependent effects, acting as a protective factor in some conditions while promoting pathogenesis in others, making it a potential therapeutic target for inflammatory diseases and certain cancers 1.