PELI3 is an E3 ubiquitin ligase that catalyzes lysine-63-linked polyubiquitination of multiple substrates to regulate innate immunity and cellular homeostasis. The protein localizes to autophagic membranes through an LC3-interacting region and mediates polyubiquitination of ULK1, a key autophagy initiator 1. PELI3 also participates in Toll-like receptor and IL-1 signaling via interaction with IRAK kinases and TRAF6, and regulates NOD1/NOD2-dependent innate immune responses through RIPK2 modification. Recent studies reveal PELI3's role in starvation-induced autophagy; genetic deletion of Peli3 in mice impairs fasting-induced hepatic autophagy and enhances hepatic steatosis, and PELI3 expression is decreased in livers of patients with metabolic dysfunction-associated steatotic liver disease 1. A protective coding variant (A307V) in PELI3 is associated with significantly reduced age-related macular degeneration risk 2. Conversely, PELI3 is aberrantly upregulated in non-small cell lung cancer, where it promotes gefitinib resistance through autophagy activation 3 and mediates pro-tumor effects downstream of dysregulated microRNAs 4. In primary Sjögren's syndrome, reduced PELI3 expression in ocular epithelial cells correlates with increased inflammation, suggesting PELI3 acts as a negative regulator of inflammatory responses 5. These findings establish PELI3 as a pleiotropic regulator with protective roles in metabolic and immune homeostasis but potentially pathogenic functions in cancer.