EPG5 (ectopic P-granules 5 autophagy tethering factor) is a metazoan-specific autophagy protein that mediates the final step of macroautophagy by promoting autophagosome-lysosome fusion 1. Structurally, EPG5 contains helical bundles analogous to membrane trafficking tethering factors, with a unique thumb domain and tandem LIR (LC3-interacting region) motifs that bind GABARAP-family Atg8 proteins to enforce fusion specificity 1. EPG5 also plays a specialized role in innate immunity by facilitating CpG dinucleotide translocation from early to late endosomes for TLR9-mediated immune responses. Additionally, EPG5 regulates selective cargo degradation; knockout in granulosa cells impairs WT1 turnover, disrupting steroidogenesis and causing primary ovarian insufficiency 2. In macrophages, EPG5 maintains homeostatic control of lung inflammation, with deficiency leading to elevated baseline innate immune activation 3.EPG5 deficiency causes Vici syndrome, a rare autosomal recessive disorder characterized by corpus callosum agenesis, congenital cataracts, cardiomyopathy, immunodeficiency, and developmental delay 4. Recently, biallelic EPG5 variants have been associated with Parkinson's disease, where deficiency impairs autophagy-lysosomal function and causes dopaminergic neurodegeneration 5. EPG5 represents a critical link between autophagy dysregulation and diverse neurodevelopmental and neurodegenerative phenotypes 67.