DEF8 (differentially expressed in FDCP 8 homolog) is a lysosomal adaptor protein that regulates autophagy and bone homeostasis. In osteoclasts, DEF8 positively regulates lysosome peripheral distribution and ruffled border formation, thereby promoting bone resorption 1. Mechanistically, DEF8 interacts with PLEKHM1 and enhances its binding to RAB7, a key regulator of lysosomal trafficking 1. This PLEKHM1/DEF8/RAB7 complex connects lysosomes to microtubules via FAM98A and NDEL1, enabling proper lysosomal positioning and secretion 1. Clinically, DEF8 dysfunction has been implicated in neurodegenerative disease. DEF8 transcription is significantly reduced in peripheral blood mononuclear cells from mild cognitive impairment and Alzheimer's disease patients, correlating with cognitive decline 2. Conversely, DEF8 protein levels are elevated in AD patient brains and Aβ42-expressing Drosophila models, suggesting upregulation under neuronal stress 3. DEF8 appears essential for maintaining cellular homeostasis during protein aggregation stress 3. Additionally, DEF8 variants show genome-wide significant associations with actinic keratosis susceptibility, potentially through pigmentation-related pathways 4. These findings position DEF8 as a multifunctional protein linking lysosomal-autophagy pathways to bone metabolism and neurodegeneration.