PELI2 is an E3 ubiquitin ligase that functions as a critical regulator of innate immunity and cellular differentiation through lysine-63-linked polyubiquitination of target proteins 1. Mechanistically, PELI2 inhibits STING signaling by binding phosphorylated STING and ubiquitinating TBK1, thereby setting a threshold for interferon production that protects against aberrant immune activation 2. During viral infection, STING-induced downregulation of PELI2 creates a positive feedback loop enabling robust antiviral responses. In lymphopoiesis, PELI2 stabilizes PU.1 and TCF3 via K63-polyubiquitination to regulate IL-7R expression, which is essential for B-cell development 1. Dysregulated PELI2 contributes to disease pathogenesis: insufficient PELI2 in lupus patients correlates with elevated interferon production 2, while a Thr257Ile variant causes constitutive NLRP3 inflammasome activation in ocular pterygium-digital keloid dysplasia 3. PELI2 loss is associated with poor prognosis in colorectal cancer, where PELI2 suppresses tumor progression via MAPK pathway inhibition 4. Additionally, PELI2 downregulation promotes B-cell acute lymphoblastic leukemia proliferation 1, and elevated PELI2 contributes to acute lung injury through inflammatory amplification 5. These findings indicate PELI2 functions as both an immune checkpoint and tumor suppressor with significant therapeutic potential.